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HLA Class I Antigen Processing Machinery Defects in Cancer Cells—Frequency, Functional Significance, and Clinical Relevance with Special Emphasis on Their Role in T Cell-Based Immunotherapy of Malignant Disease

Protocol
First Online:
Part of the Methods in Molecular Biology book series (MIMB, volume 2055)

Abstract

MHC class I antigen abnormalities have been shown to be one of the major immune escape mechanisms murine and human cancer cells utilize to avoid recognition and destruction by host immune system. This mechanism has clinical relevance, since it is associated with poor prognosis and/or reduced patients’ survival in many types of malignant diseases. The recent impressive clinical responses to T cell-based immunotherapies triggered by checkpoint inhibitors have rekindled tumor immunologists and clinical oncologists’ interest in the analysis of the human leukocyte antigen (HLA) class I antigen processing machinery (APM) expression and function in malignant cells. Abnormalities in the expression, regulation and/or function of components of this machinery have been associated with the development of resistances to T cell-based immunotherapies. In this review, following the description of the human leukocyte antigen (HLA) class I APM organization and function, the information related to the frequency of defects in HLA class I APM component expression in various types of cancer and the underlying molecular mechanisms is summarized. Then the impact of these defects on clinical response to T cell-based immunotherapies and strategies to revert this immune escape process are discussed.

Key words

Antigen processing machinery HLA class I Immune escape Immune response MHC Prognostic marker Tumor surveillance 

Abbreviations

ACT

Adoptive T cell therapy

APLNR

Apelin receptor

APM

Antigen processing machinery

BGN

Biglycan

CNX

Calnexin

CRC

Colorectal cancer

CRT

Calreticulin

CTL

Cytotoxic T lymphocyte

ECM

Extracellular matrix

EMT

Epithelial–mesenchymal transition

ERAP

ER-resident aminopeptidases

ER

Endoplasmic reticulum

HC

Heavy chain

HDAC

Histone deacetylase

HDACi

Histone deacetylase inhibitors

HLA

Human leukocyte antigen

HNSCC

Head and neck squamous cancer

iCP

Immune checkpoint

iCPI

Immune checkpoint inhibitor

IHC

Immunohistochemistry

IFN

Interferon

JAK

Janus kinase

LOH

Loss of heterozygosity

LMP

Low molecular weight proteins

mAb

Monoclonal antibody

miRNAs

MicroRNAs

NLRC5

NOD-like receptor caspase recruitment domain containing protein 5

NSCLC

Non-small cell lung carcinoma

OS

Overall survival

PLC

Peptide loading complex

RBP

RNA-binding proteins

RCC

Renal cell carcinoma

SNP

Single nucleotide polymorphisms

TA

Tumor antigen

TAP

Transporter associated with antigen processing

TIL

Tumor-infiltrating lymphocyte

TNBC

Triple negative breast cancer

tpn

Tapasin

UCP2

Uncoupling protein 2

β2-m

β2-microglobulin

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References

  1. 1.
    Reeves E, James E (2017) Antigen processing and immune regulation in the response to tumours. Immunology 150(1):16–24.  https://doi.org/10.1111/imm.12675PubMedCrossRefGoogle Scholar
  2. 2.
    Cai L, Michelakos T, Yamada T, Fan S, Wang X, Schwab JH, Ferrone CR, Ferrone S (2018) Defective HLA class I antigen processing machinery in cancer. Cancer Immunol Immunother 67(6):999–1009.  https://doi.org/10.1007/s00262-018-2131-2PubMedCrossRefGoogle Scholar
  3. 3.
    Diesendruck Y, Benhar I (2017) Novel immune check point inhibiting antibodies in cancer therapy-opportunities and challenges. Drug Resist Updat 30:39–47.  https://doi.org/10.1016/j.drup.2017.02.001PubMedCrossRefGoogle Scholar
  4. 4.
    Perez-Gracia JL, Labiano S, Rodriguez-Ruiz ME, Sanmamed MF, Melero I (2014) Orchestrating immune check-point blockade for cancer immunotherapy in combinations. Curr Opin Immunol 27:89–97.  https://doi.org/10.1016/j.coi.2014.01.002PubMedCrossRefGoogle Scholar
  5. 5.
    Emens LA, Ascierto PA, Darcy PK, Demaria S, Eggermont AMM, Redmond WL, Seliger B, Marincola FM (2017) Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer 81:116–129.  https://doi.org/10.1016/j.ejca.2017.01.035PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Wennerberg E, Lhuillier C, Vanpouille-Box C, Pilones KA, Garcia-Martinez E, Rudqvist NP, Formenti SC, Demaria S (2017) Barriers to radiation-induced in situ tumor vaccination. Front Immunol 8:229.  https://doi.org/10.3389/fimmu.2017.00229PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Leone P, Shin EC, Perosa F, Vacca A, Dammacco F, Racanelli V (2013) MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J Natl Cancer Inst 105(16):1172–1187.  https://doi.org/10.1093/jnci/djt184PubMedCrossRefGoogle Scholar
  8. 8.
    Ortiz-Navarrete V, Seelig A, Gernold M, Frentzel S, Kloetzel PM, Hammerling GJ (1991) Subunit of the ‘20S’ proteasome (multicatalytic proteinase) encoded by the major histocompatibility complex. Nature 353(6345):662–664.  https://doi.org/10.1038/353662a0PubMedCrossRefGoogle Scholar
  9. 9.
    Kelly A, Powis SH, Glynne R, Radley E, Beck S, Trowsdale J (1991) Second proteasome-related gene in the human MHC class II region. Nature 353(6345):667–668.  https://doi.org/10.1038/353667a0PubMedCrossRefGoogle Scholar
  10. 10.
    Neefjes JJ, Momburg F, Hammerling GJ (1993) Selective and ATP-dependent translocation of peptides by the MHC-encoded transporter. Science 261(5122):769–771PubMedCrossRefGoogle Scholar
  11. 11.
    Blees A, Januliene D, Hofmann T, Koller N, Schmidt C, Trowitzsch S, Moeller A, Tampe R (2017) Structure of the human MHC-I peptide-loading complex. Nature 551(7681):525–528.  https://doi.org/10.1038/nature24627PubMedCrossRefGoogle Scholar
  12. 12.
    Vassilakos A, Cohen-Doyle MF, Peterson PA, Jackson MR, Williams DB (1996) The molecular chaperone calnexin facilitates folding and assembly of class I histocompatibility molecules. EMBO J 15(7):1495–1506PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Leonhardt RM, Abrahimi P, Mitchell SM, Cresswell P (2014) Three tapasin docking sites in TAP cooperate to facilitate transporter stabilization and heterodimerization. J Immunol 192(5):2480–2494.  https://doi.org/10.4049/jimmunol.1302637PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Purcell AW, Gorman JJ, Garcia-Peydro M, Paradela A, Burrows SR, Talbo GH, Laham N, Peh CA, Reynolds EC, Lopez De Castro JA, McCluskey J (2001) Quantitative and qualitative influences of tapasin on the class I peptide repertoire. J Immunol 166(2):1016–1027PubMedCrossRefGoogle Scholar
  15. 15.
    Kanaseki T, Lind KC, Escobar H, Nagarajan N, Reyes-Vargas E, Rudd B, Rockwood AL, Van Kaer L, Sato N, Delgado JC, Shastri N (2013) ERAAP and tapasin independently edit the amino and carboxyl termini of MHC class I peptides. J Immunol 191(4):1547–1555.  https://doi.org/10.4049/jimmunol.1301043PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Eichmuller SB, Osen W, Mandelboim O, Seliger B (2017) Immune modulatory microRNAs involved in tumor attack and tumor immune escape. J Natl Cancer Inst 109(10).  https://doi.org/10.1093/jnci/djx034
  17. 17.
    Reches A, Nachmani D, Berhani O, Duev-Cohen A, Shreibman D, Ophir Y, Seliger B, Mandelboim O (2016) HNRNPR regulates the expression of classical and nonclassical MHC class I proteins. J Immunol 196(12):4967–4976.  https://doi.org/10.4049/jimmunol.1501550PubMedCrossRefGoogle Scholar
  18. 18.
    Huang L, Malu S, McKenzie JA, Andrews MC, Talukder AH, Tieu T, Karpinets T, Haymaker C, Forget MA, Williams LJ, Wang Z, Mbofung RM, Wang ZQ, Davis RE, Lo RS, Wargo JA, Davies MA, Bernatchez C, Heffernan T, Amaria RN, Korkut A, Peng W, Roszik J, Lizee G, Woodman SE, Hwu P (2018) The RNA-binding protein MEX3B mediates resistance to cancer immunotherapy by downregulating HLA-A expression. Clin Cancer Res 24(14):3366–3376.  https://doi.org/10.1158/1078-0432.CCR-17-2483PubMedCrossRefGoogle Scholar
  19. 19.
    Hicklin DJ, Kageshita T, Ferrone S (1996) Development and characterization of rabbit antisera to human MHC-linked transporters associated with antigen processing. Tissue Antigens 48(1):38–46PubMedCrossRefGoogle Scholar
  20. 20.
    Bandoh N, Ogino T, Cho HS, Hur SY, Shen J, Wang X, Kato S, Miyokawa N, Harabuchi Y, Ferrone S (2005) Development and characterization of human constitutive proteasome and immunoproteasome subunit-specific monoclonal antibodies. Tissue Antigens 66(3):185–194.  https://doi.org/10.1111/j.1399-0039.2005.00462.xPubMedCrossRefGoogle Scholar
  21. 21.
    Ogino T, Wang X, Kato S, Miyokawa N, Harabuchi Y, Ferrone S (2003) Endoplasmic reticulum chaperone-specific monoclonal antibodies for flow cytometry and immunohistochemical staining. Tissue Antigens 62(5):385–393PubMedCrossRefGoogle Scholar
  22. 22.
    Stam NJ, Spits H, Ploegh HL (1986) Monoclonal antibodies raised against denatured HLA-B locus heavy chains permit biochemical characterization of certain HLA-C locus products. J Immunol 137(7):2299–2306PubMedGoogle Scholar
  23. 23.
    Brodsky FM, Bodmer WF, Parham P (1979) Characterization of a monoclonal anti-beta 2-microglobulin antibody and its use in the genetic and biochemical analysis of major histocompatibility antigens. Eur J Immunol 9(7):536–545.  https://doi.org/10.1002/eji.1830090709PubMedCrossRefGoogle Scholar
  24. 24.
    Parham P, Barnstable CJ, Bodmer WF (1979) Use of a monoclonal antibody (W6/32) in structural studies of HLA-A,B,C, antigens. J Immunol 123(1):342–349PubMedGoogle Scholar
  25. 25.
    Feng Z, Bethmann D, Kappler M, Ballesteros-Merino C, Eckert A, Bell RB, Cheng A, Bui T, Leidner R, Urba WJ, Johnson K, Hoyt C, Bifulco CB, Bukur J, Wickenhauser C, Seliger B, Fox BA (2017) Multiparametric immune profiling in HPV- oral squamous cell cancer. JCI Insight 2(14).  https://doi.org/10.1172/jci.insight.93652
  26. 26.
    Meissner TB, Li A, Kobayashi KS (2012) NLRC5: a newly discovered MHC class I transactivator (CITA). Microbes Infect 14(6):477–484.  https://doi.org/10.1016/j.micinf.2011.12.007PubMedCrossRefGoogle Scholar
  27. 27.
    Meissner TB, Li A, Biswas A, Lee KH, Liu YJ, Bayir E, Iliopoulos D, van den Elsen PJ, Kobayashi KS (2010) NLR family member NLRC5 is a transcriptional regulator of MHC class I genes. Proc Natl Acad Sci U S A 107(31):13794–13799.  https://doi.org/10.1073/pnas.1008684107PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Yoshihama S, Roszik J, Downs I, Meissner TB, Vijayan S, Chapuy B, Sidiq T, Shipp MA, Lizee GA, Kobayashi KS (2016) NLRC5/MHC class I transactivator is a target for immune evasion in cancer. Proc Natl Acad Sci U S A 113(21):5999–6004.  https://doi.org/10.1073/pnas.1602069113PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Vermeulen CF, Jordanova ES, Zomerdijk-Nooijen YA, ter Haar NT, Peters AA, Fleuren GJ (2005) Frequent HLA class I loss is an early event in cervical carcinogenesis. Hum Immunol 66(11):1167–1173.  https://doi.org/10.1016/j.humimm.2005.10.011PubMedCrossRefGoogle Scholar
  30. 30.
    Inoue M, Mimura K, Izawa S, Shiraishi K, Inoue A, Shiba S, Watanabe M, Maruyama T, Kawaguchi Y, Inoue S, Kawasaki T, Choudhury A, Katoh R, Fujii H, Kiessling R, Kono K (2012) Expression of MHC Class I on breast cancer cells correlates inversely with HER2 expression. Oncoimmunology 1(7):1104–1110.  https://doi.org/10.4161/onci.21056PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Hanagiri T, Shigematsu Y, Shinohara S, Takenaka M, Oka S, Chikaishi Y, Nagata Y, Baba T, Uramoto H, So T, Yamada S (2013) Clinical significance of expression of cancer/testis antigen and down-regulation of HLA class-I in patients with stage I non-small cell lung cancer. Anticancer Res 33(5):2123–2128PubMedGoogle Scholar
  32. 32.
    McGranahan N, Rosenthal R, Hiley CT, Rowan AJ, Watkins TBK, Wilson GA, Birkbak NJ, Veeriah S, Van Loo P, Herrero J, Swanton C, Consortium TR (2017) Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171(6):1259–1271 e1211.  https://doi.org/10.1016/j.cell.2017.10.001PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Maeurer MJ, Gollin SM, Storkus WJ, Swaney W, Karbach J, Martin D, Castelli C, Salter R, Knuth A, Lotze MT (1996) Tumor escape from immune recognition: loss of HLA-A2 melanoma cell surface expression is associated with a complex rearrangement of the short arm of chromosome 6. Clin Cancer Res 2(4):641–652PubMedGoogle Scholar
  34. 34.
    Seliger B, Ritz U, Abele R, Bock M, Tampe R, Sutter G, Drexler I, Huber C, Ferrone S (2001) Immune escape of melanoma: first evidence of structural alterations in two distinct components of the MHC class I antigen processing pathway. Cancer Res 61(24):8647–8650PubMedGoogle Scholar
  35. 35.
    Leo PJ, Madeleine MM, Wang S, Schwartz SM, Newell F, Pettersson-Kymmer U, Hemminki K, Hallmans G, Tiews S, Steinberg W, Rader JS, Castro F, Safaeian M, Franco EL, Coutlee F, Ohlsson C, Cortes A, Marshall M, Mukhopadhyay P, Cremin K, Johnson LG, Trimble CL, Garland S, Tabrizi SN, Wentzensen N, Sitas F, Little J, Cruickshank M, Frazer IH, Hildesheim A, Brown MA (2017) Defining the genetic susceptibility to cervical neoplasia-a genome-wide association study. PLoS Genet 13(8):e1006866.  https://doi.org/10.1371/journal.pgen.1006866PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Das Ghosh D, Mukhopadhyay I, Bhattacharya A, Roy Chowdhury R, Mandal NR, Roy S, Sengupta S (2017) Impact of genetic variations and transcriptional alterations of HLA class I genes on cervical cancer pathogenesis. Int J Cancer 140(11):2498–2508.  https://doi.org/10.1002/ijc.30681PubMedCrossRefGoogle Scholar
  37. 37.
    Florea ID, Karaoulani C (2018) Epigenetic changes of the immune system with role in tumor development. Methods Mol Biol 1856:203–218.  https://doi.org/10.1007/978-1-4939-8751-1_11PubMedCrossRefGoogle Scholar
  38. 38.
    Sheehan RG, Balaban EP, Frenkel EP (1993) The impact of dose intensity of standard chemotherapy regimens in extensive stage small cell lung cancer. Am J Clin Oncol 16(3):250–255PubMedCrossRefGoogle Scholar
  39. 39.
    Kamphausen E, Kellert C, Abbas T, Akkad N, Tenzer S, Pawelec G, Schild H, van Endert P, Seliger B (2010) Distinct molecular mechanisms leading to deficient expression of ER-resident aminopeptidases in melanoma. Cancer Immunol Immunother 59(8):1273–1284.  https://doi.org/10.1007/s00262-010-0856-7PubMedCrossRefGoogle Scholar
  40. 40.
    James E, Bailey I, Sugiyarto G, Elliott T (2013) Induction of protective antitumor immunity through attenuation of ERAAP function. J Immunol 190(11):5839–5846.  https://doi.org/10.4049/jimmunol.1300220PubMedCrossRefGoogle Scholar
  41. 41.
    Cromme FV, Airey J, Heemels MT, Ploegh HL, Keating PJ, Stern PL, Meijer CJ, Walboomers JM (1994) Loss of transporter protein, encoded by the TAP-1 gene, is highly correlated with loss of HLA expression in cervical carcinomas. J Exp Med 179(1):335–340PubMedCrossRefGoogle Scholar
  42. 42.
    Seliger B, Hohne A, Knuth A, Bernhard H, Ehring B, Tampe R, Huber C (1996) Reduced membrane major histocompatibility complex class I density and stability in a subset of human renal cell carcinomas with low TAP and LMP expression. Clin Cancer Res 2(8):1427–1433PubMedGoogle Scholar
  43. 43.
    Seliger B, Atkins D, Bock M, Ritz U, Ferrone S, Huber C, Storkel S (2003) Characterization of human lymphocyte antigen class I antigen-processing machinery defects in renal cell carcinoma lesions with special emphasis on transporter-associated with antigen-processing down-regulation. Clin Cancer Res 9(5):1721–1727PubMedGoogle Scholar
  44. 44.
    Ritz U, Momburg F, Pilch H, Huber C, Maeurer MJ, Seliger B (2001) Deficient expression of components of the MHC class I antigen processing machinery in human cervical carcinoma. Int J Oncol 19(6):1211–1220PubMedGoogle Scholar
  45. 45.
    Ling A, Lofgren-Burstrom A, Larsson P, Li X, Wikberg ML, Oberg A, Stenling R, Edin S, Palmqvist R (2017) TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer. Oncoimmunology 6(11):e1356143.  https://doi.org/10.1080/2162402X.2017.1356143PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Kaklamanis L, Townsend A, Doussis-Anagnostopoulou IA, Mortensen N, Harris AL, Gatter KC (1994) Loss of major histocompatibility complex-encoded transporter associated with antigen presentation (TAP) in colorectal cancer. Am J Pathol 145(3):505–509PubMedPubMedCentralGoogle Scholar
  47. 47.
    Androlewicz MJ, Ortmann B, van Endert PM, Spies T, Cresswell P (1994) Characteristics of peptide and major histocompatibility complex class I/beta 2-microglobulin binding to the transporters associated with antigen processing (TAP1 and TAP2). Proc Natl Acad Sci U S A 91(26):12716–12720PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kallfelz M, Jung D, Hilmes C, Knuth A, Jaeger E, Huber C, Seliger B (1999) Induction of immunogenicity of a human renal-cell carcinoma cell line by TAP1-gene transfer. Int J Cancer 81(1):125–133PubMedCrossRefGoogle Scholar
  49. 49.
    Williams AP, Peh CA, Purcell AW, McCluskey J, Elliott T (2002) Optimization of the MHC class I peptide cargo is dependent on tapasin. Immunity 16(4):509–520PubMedCrossRefGoogle Scholar
  50. 50.
    Shionoya Y, Kanaseki T, Miyamoto S, Tokita S, Hongo A, Kikuchi Y, Kochin V, Watanabe K, Horibe R, Saijo H, Tsukahara T, Hirohashi Y, Takahashi H, Sato N, Torigoe T (2017) Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition. Oncoimmunology 6(2):e1274476.  https://doi.org/10.1080/2162402X.2016.1274476PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Harvey DJ (1975) Examination of the diphenylpropanoids of nutmeg as their trimethylsilyl, triethylsilyl and tri-n-propylsilyl derivatives using combined gas chromatography and mass spectrometry. J Chromatogr 110(1):91–102PubMedCrossRefGoogle Scholar
  52. 52.
    Yoshihama S, Vijayan S, Sidiq T, Kobayashi KS (2017) NLRC5/CITA: a key player in cancer immune surveillance. Trends Cancer 3(1):28–38.  https://doi.org/10.1016/j.trecan.2016.12.003PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Kiewe P, Mansmann V, Scheibenbogen C, Buhr HJ, Thiel E, Nagorsen D (2008) HLA-A2 expression, stage, and survival in colorectal cancer. Int J Colorectal Dis 23(8):767–772.  https://doi.org/10.1007/s00384-008-0488-yPubMedCrossRefGoogle Scholar
  54. 54.
    Tripathi SC, Peters HL, Taguchi A, Katayama H, Wang H, Momin A, Jolly MK, Celiktas M, Rodriguez-Canales J, Liu H, Behrens C, Wistuba II, Ben-Jacob E, Levine H, Molldrem JJ, Hanash SM, Ostrin EJ (2016) Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome. Proc Natl Acad Sci U S A 113(11):E1555–E1564.  https://doi.org/10.1073/pnas.1521812113PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Seliger B, Stoehr R, Handke D, Mueller A, Ferrone S, Wullich B, Tannapfel A, Hofstaedter F, Hartmann A (2010) Association of HLA class I antigen abnormalities with disease progression and early recurrence in prostate cancer. Cancer Immunol Immunother 59(4):529–540.  https://doi.org/10.1007/s00262-009-0769-5PubMedCrossRefGoogle Scholar
  56. 56.
    Mehta AM, Jordanova ES, van Wezel T, Uh HW, Corver WE, Kwappenberg KM, Verduijn W, Kenter GG, van der Burg SH, Fleuren GJ (2007) Genetic variation of antigen processing machinery components and association with cervical carcinoma. Genes Chromosomes Cancer 46(6):577–586.  https://doi.org/10.1002/gcc.20441PubMedCrossRefGoogle Scholar
  57. 57.
    Mehta AM, Jordanova ES, Corver WE, van Wezel T, Uh HW, Kenter GG, Jan Fleuren G (2009) Single nucleotide polymorphisms in antigen processing machinery component ERAP1 significantly associate with clinical outcome in cervical carcinoma. Genes Chromosomes Cancer 48(5):410–418.  https://doi.org/10.1002/gcc.20648PubMedCrossRefGoogle Scholar
  58. 58.
    Pedersen MH, Hood BL, Beck HC, Conrads TP, Ditzel HJ, Leth-Larsen R (2017) Downregulation of antigen presentation-associated pathway proteins is linked to poor outcome in triple-negative breast cancer patient tumors. Oncoimmunology 6(5):e1305531.  https://doi.org/10.1080/2162402X.2017.1305531PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Johnsen AK, Templeton DJ, Sy M, Harding CV (1999) Deficiency of transporter for antigen presentation (TAP) in tumor cells allows evasion of immune surveillance and increases tumorigenesis. J Immunol 163(8):4224–4231PubMedGoogle Scholar
  60. 60.
    Kamarashev J, Ferrone S, Seifert B, Boni R, Nestle FO, Burg G, Dummer R (2001) TAP1 down-regulation in primary melanoma lesions: an independent marker of poor prognosis. Int J Cancer 95(1):23–28PubMedCrossRefGoogle Scholar
  61. 61.
    Bandoh N, Ogino T, Katayama A, Takahara M, Katada A, Hayashi T, Harabuchi Y (2010) HLA class I antigen and transporter associated with antigen processing downregulation in metastatic lesions of head and neck squamous cell carcinoma as a marker of poor prognosis. Oncol Rep 23(4):933–939PubMedCrossRefGoogle Scholar
  62. 62.
    Tanaka K, Tsuchikawa T, Miyamoto M, Maki T, Ichinokawa M, Kubota KC, Shichinohe T, Hirano S, Ferrone S, Dosaka-Akita H, Matsuno Y, Kondo S (2012) Down-regulation of human leukocyte antigen class I heavy chain in tumors is associated with a poor prognosis in advanced esophageal cancer patients. Int J Oncol 40(4):965–974.  https://doi.org/10.3892/ijo.2011.1274PubMedCrossRefGoogle Scholar
  63. 63.
    Meissner M, Reichert TE, Kunkel M, Gooding W, Whiteside TL, Ferrone S, Seliger B (2005) Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcome. Clin Cancer Res 11(7):2552–2560.  https://doi.org/10.1158/1078-0432.CCR-04-2146PubMedCrossRefGoogle Scholar
  64. 64.
    Kageshita T, Hirai S, Ono T, Hicklin DJ, Ferrone S (1999) Down-regulation of HLA class I antigen-processing molecules in malignant melanoma: association with disease progression. Am J Pathol 154(3):745–754.  https://doi.org/10.1016/S0002-9440(10)65321-7PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Lou Y, Vitalis TZ, Basha G, Cai B, Chen SS, Choi KB, Jeffries AP, Elliott WM, Atkins D, Seliger B, Jefferies WA (2005) Restoration of the expression of transporters associated with antigen processing in lung carcinoma increases tumor-specific immune responses and survival. Cancer Res 65(17):7926–7933.  https://doi.org/10.1158/0008-5472.CAN-04-3977PubMedCrossRefGoogle Scholar
  66. 66.
    Meng J, Li W, Zhang M, Hao Z, Fan S, Zhang L, Liang C (2018) An update meta-analysis and systematic review of TAP polymorphisms as potential biomarkers for judging cancer risk. Pathol Res Pract 214(10):1556–1563.  https://doi.org/10.1016/j.prp.2018.07.018PubMedCrossRefGoogle Scholar
  67. 67.
    Chung H, Cho H, Perry C, Song J, Ylaya K, Lee H, Kim JH (2013) Downregulation of ERp57 expression is associated with poor prognosis in early-stage cervical cancer. Biomarkers 18(7):573–579.  https://doi.org/10.3109/1354750X.2013.827742PubMedCrossRefGoogle Scholar
  68. 68.
    Leys CM, Nomura S, LaFleur BJ, Ferrone S, Kaminishi M, Montgomery E, Goldenring JR (2007) Expression and prognostic significance of prothymosin-alpha and ERp57 in human gastric cancer. Surgery 141(1):41–50.  https://doi.org/10.1016/j.surg.2006.05.009PubMedCrossRefGoogle Scholar
  69. 69.
    Romero JM, Jimenez P, Cabrera T, Cozar JM, Pedrinaci S, Tallada M, Garrido F, Ruiz-Cabello F (2005) Coordinated downregulation of the antigen presentation machinery and HLA class I/beta2-microglobulin complex is responsible for HLA-ABC loss in bladder cancer. Int J Cancer 113(4):605–610.  https://doi.org/10.1002/ijc.20499PubMedCrossRefGoogle Scholar
  70. 70.
    Sokol L, Koelzer VH, Rau TT, Karamitopoulou E, Zlobec I, Lugli A (2015) Loss of tapasin correlates with diminished CD8(+) T-cell immunity and prognosis in colorectal cancer. J Transl Med 13:279.  https://doi.org/10.1186/s12967-015-0647-1PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Dissemond J, Kothen T, Mors J, Weimann TK, Lindeke A, Goos M, Wagner SN (2003) Downregulation of tapasin expression in progressive human malignant melanoma. Arch Dermatol Res 295(2):43–49.  https://doi.org/10.1007/s00403-003-0393-8PubMedCrossRefGoogle Scholar
  72. 72.
    Turnquist HR, Kohlgraf KG, McIlhaney MM, Mosley RL, Hollingsworth MA, Solheim JC (2004) Tapasin decreases immune responsiveness to a model tumor antigen. J Clin Immunol 24(4):462–470.  https://doi.org/10.1023/B:JOCI.0000029118.51587.d9PubMedCrossRefGoogle Scholar
  73. 73.
    Li X, Guo F, Liu Y, Chen HJ, Wen F, Zou B, Li D, Qin Q, Liu X, Shen Y, Wang Y (2015) NLRC5 expression in tumors and its role as a negative prognostic indicator in stage III non-small-cell lung cancer patients. Oncol Lett 10(3):1533–1540.  https://doi.org/10.3892/ol.2015.3471PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Seliger B (2012) Novel insights into the molecular mechanisms of HLA class I abnormalities. Cancer Immunol Immunother 61(2):249–254.  https://doi.org/10.1007/s00262-011-1153-9PubMedCrossRefGoogle Scholar
  75. 75.
    Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A (2017) Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168(4):707–723.  https://doi.org/10.1016/j.cell.2017.01.017PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Pitt JM, Vetizou M, Daillere R, Roberti MP, Yamazaki T, Routy B, Lepage P, Boneca IG, Chamaillard M, Kroemer G, Zitvogel L (2016) Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors. Immunity 44(6):1255–1269.  https://doi.org/10.1016/j.immuni.2016.06.001PubMedCrossRefGoogle Scholar
  77. 77.
    Ribas A (2015) Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov 5(9):915–919.  https://doi.org/10.1158/2159-8290.CD-15-0563PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Gide TN, Wilmott JS, Scolyer RA, Long GV (2018) Primary and acquired resistance to immune checkpoint inhibitors in metastatic melanoma. Clin Cancer Res 24(6):1260–1270.  https://doi.org/10.1158/1078-0432.CCR-17-2267PubMedCrossRefGoogle Scholar
  79. 79.
    Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C (2017) Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 390(10105):1853–1862.  https://doi.org/10.1016/S0140-6736(17)31601-XPubMedCrossRefGoogle Scholar
  80. 80.
    Aptsiauri N, Carretero R, Garcia-Lora A, Real LM, Cabrera T, Garrido F (2008) Regressing and progressing metastatic lesions: resistance to immunotherapy is predetermined by irreversible HLA class I antigen alterations. Cancer Immunol Immunother 57(11):1727–1733.  https://doi.org/10.1007/s00262-008-0532-3PubMedCrossRefGoogle Scholar
  81. 81.
    D’Urso CM, Wang ZG, Cao Y, Tatake R, Zeff RA, Ferrone S (1991) Lack of HLA class I antigen expression by cultured melanoma cells FO-1 due to a defect in B2m gene expression. J Clin Invest 87(1):284–292.  https://doi.org/10.1172/JCI114984PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Restifo NP, Marincola FM, Kawakami Y, Taubenberger J, Yannelli JR, Rosenberg SA (1996) Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J Natl Cancer Inst 88(2):100–108PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Ohnmacht GA, Wang E, Mocellin S, Abati A, Filie A, Fetsch P, Riker AI, Kammula US, Rosenberg SA, Marincola FM (2001) Short-term kinetics of tumor antigen expression in response to vaccination. J Immunol 167(3):1809–1820PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, Pasetto A, Zheng Z, Ray S, Groh EM, Kriley IR, Rosenberg SA (2016) T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med 375(23):2255–2262.  https://doi.org/10.1056/NEJMoa1609279PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Schrors B, Lubcke S, Lennerz V, Fatho M, Bicker A, Wolfel C, Derigs P, Hankeln T, Schadendorf D, Paschen A, Wolfel T (2017) HLA class I loss in metachronous metastases prevents continuous T cell recognition of mutated neoantigens in a human melanoma model. Oncotarget 8(17):28312–28327.  https://doi.org/10.18632/oncotarget.16048PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, Sandoval S, Barthly L, Saco J, Homet Moreno B, Mezzadra R, Chmielowski B, Ruchalski K, Shintaku IP, Sanchez PJ, Puig-Saus C, Cherry G, Seja E, Kong X, Pang J, Berent-Maoz B, Comin-Anduix B, Graeber TG, Tumeh PC, Schumacher TN, Lo RS, Ribas A (2016) Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 375(9):819–829.  https://doi.org/10.1056/NEJMoa1604958PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Gettinger S, Choi J, Hastings K, Truini A, Datar I, Sowell R, Wurtz A, Dong W, Cai G, Melnick MA, Du VY, Schlessinger J, Goldberg SB, Chiang A, Sanmamed MF, Melero I, Agorreta J, Montuenga LM, Lifton R, Ferrone S, Kavathas P, Rimm DL, Kaech SM, Schalper K, Herbst RS, Politi K (2017) Impaired HLA class i antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov 7(12):1420–1435.  https://doi.org/10.1158/2159-8290.CD-17-0593PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Alsufyani F, Pillai S (2017) JAKing up resistance to immunotherapy. Sci Immunol 2(16).  https://doi.org/10.1126/sciimmunol.aaq0015PubMedCrossRefGoogle Scholar
  89. 89.
    Paulson KG, Voillet V, McAfee MS, Hunter DS, Wagener FD, Perdicchio M, Valente WJ, Koelle SJ, Church CD, Vandeven N, Thomas H, Colunga AG, Iyer JG, Yee C, Kulikauskas R, Koelle DM, Pierce RH, Bielas JH, Greenberg PD, Bhatia S, Gottardo R, Nghiem P, Chapuis AG (2018) Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA. Nat Commun 9(1):3868.  https://doi.org/10.1038/s41467-018-06300-3PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Donia M, Harbst K, van Buuren M, Kvistborg P, Lindberg MF, Andersen R, Idorn M, Munir Ahmad S, Ellebaek E, Mueller A, Fagone P, Nicoletti F, Libra M, Lauss M, Hadrup SR, Schmidt H, Andersen MH, Thor Straten P, Nilsson JA, Schumacher TN, Seliger B, Jonsson G, Svane IM (2017) Acquired immune resistance follows complete tumor regression without loss of target antigens or ifngamma signaling. Cancer Res 77(17):4562–4566.  https://doi.org/10.1158/0008-5472.CAN-16-3172PubMedCrossRefGoogle Scholar
  91. 91.
    Johnson DB, Nixon MJ, Wang Y, Wang DY, Castellanos E, Estrada MV, Ericsson-Gonzalez PI, Cote CH, Salgado R, Sanchez V, Dean PT, Opalenik SR, Schreeder DM, Rimm DL, Kim JY, Bordeaux J, Loi S, Horn L, Sanders ME, Ferrell PB Jr, Xu Y, Sosman JA, Davis RS, Balko JM (2018) Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement. JCI Insight 3(24).  https://doi.org/10.1172/jci.insight.120360
  92. 92.
    Terry S, Savagner P, Ortiz-Cuaran S, Mahjoubi L, Saintigny P, Thiery JP, Chouaib S (2017) New insights into the role of EMT in tumor immune escape. Mol Oncol 11(7):824–846.  https://doi.org/10.1002/1878-0261.12093PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Shields BD, Mahmoud F, Taylor EM, Byrum SD, Sengupta D, Koss B, Baldini G, Ransom S, Cline K, Mackintosh SG, Edmondson RD, Shalin S, Tackett AJ (2017) Indicators of responsiveness to immune checkpoint inhibitors. Sci Rep 7(1):807.  https://doi.org/10.1038/s41598-017-01000-2PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Arenas-Ramirez N, Sahin D, Boyman O (2018) Epigenetic mechanisms of tumor resistance to immunotherapy. Cell Mol Life Sci 75(22):4163–4176.  https://doi.org/10.1007/s00018-018-2908-7PubMedCrossRefGoogle Scholar
  95. 95.
    Moon EK, Wang LC, Dolfi DV, Wilson CB, Ranganathan R, Sun J, Kapoor V, Scholler J, Pure E, Milone MC, June CH, Riley JL, Wherry EJ, Albelda SM (2014) Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res 20(16):4262–4273.  https://doi.org/10.1158/1078-0432.CCR-13-2627PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Ninomiya S, Narala N, Huye L, Yagyu S, Savoldo B, Dotti G, Heslop HE, Brenner MK, Rooney CM, Ramos CA (2015) Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood 125(25):3905–3916.  https://doi.org/10.1182/blood-2015-01-621474PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Keller HR, Zhang X, Li L, Schaider H, Wells JW (2017) Overcoming resistance to targeted therapy with immunotherapy and combination therapy for metastatic melanoma. Oncotarget 8(43):75675–75686.  https://doi.org/10.18632/oncotarget.18523PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Lou Y, Basha G, Seipp RP, Cai B, Chen SS, Moise AR, Jeffries AP, Gopaul RS, Vitalis TZ, Jefferies WA (2008) Combining the antigen processing components TAP and Tapasin elicits enhanced tumor-free survival. Clin Cancer Res 14(5):1494–1501.  https://doi.org/10.1158/1078-0432.CCR-07-1066PubMedCrossRefGoogle Scholar
  99. 99.
    Seliger B, Wollscheid U, Momburg F, Blankenstein T, Huber C (2001) Characterization of the major histocompatibility complex class I deficiencies in B16 melanoma cells. Cancer Res 61(3):1095–1099PubMedGoogle Scholar
  100. 100.
    Rodriguez GM, Bobbala D, Serrano D, Mayhue M, Champagne A, Saucier C, Steimle V, Kufer TA, Menendez A, Ramanathan S, Ilangumaran S (2016) NLRC5 elicits antitumor immunity by enhancing processing and presentation of tumor antigens to CD8(+) T lymphocytes. Oncoimmunology 5(6):e1151593.  https://doi.org/10.1080/2162402X.2016.1151593PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Bukur J, Herrmann F, Handke D, Recktenwald C, Seliger B (2010) Identification of E2F1 as an important transcription factor for the regulation of tapasin expression. J Biol Chem 285(40):30419–30426.  https://doi.org/10.1074/jbc.M109.094284PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Zervoudi E, Saridakis E, Birtley JR, Seregin SS, Reeves E, Kokkala P, Aldhamen YA, Amalfitano A, Mavridis IM, James E, Georgiadis D, Stratikos E (2013) Rationally designed inhibitor targeting antigen-trimming aminopeptidases enhances antigen presentation and cytotoxic T-cell responses. Proc Natl Acad Sci U S A 110(49):19890–19895.  https://doi.org/10.1073/pnas.1309781110PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Mushtaq MU, Papadas A, Pagenkopf A, Flietner E, Morrow Z, Chaudhary SG, Asimakopoulos F (2018) Tumor matrix remodeling and novel immunotherapies: the promise of matrix-derived immune biomarkers. J Immunother Cancer 6(1):65.  https://doi.org/10.1186/s40425-018-0376-0PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Subbarayan K, Leisz S, Wickenhauser C, Bethmann D, Massa C, Steven A, Seliger B (2018) Biglycan-mediated upregulation of MHC class I expression in HER-2/neu-transformed cells. Oncoimmunology 7(4):e1373233.  https://doi.org/10.1080/2162402X.2017.1373233PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Recktenwald CV, Mendler S, Lichtenfels R, Kellner R, Seliger B (2007) Influence of Ki-ras-driven oncogenic transformation on the protein network of murine fibroblasts. Proteomics 7(3):385–398.  https://doi.org/10.1002/pmic.200600506PubMedCrossRefGoogle Scholar
  106. 106.
    Seliger B, Dunn T, Schwenzer A, Casper J, Huber C, Schmoll HJ (1997) Analysis of the MHC class I antigen presentation machinery in human embryonal carcinomas: evidence for deficiencies in TAP, LMP and MHC class I expression and their upregulation by IFN-gamma. Scand J Immunol 46(6):625–632PubMedCrossRefGoogle Scholar
  107. 107.
    Fruh K, Yang Y (1999) Antigen presentation by MHC class I and its regulation by interferon gamma. Curr Opin Immunol 11(1):76–81PubMedCrossRefGoogle Scholar
  108. 108.
    Decker T, Kovarik P, Meinke A (1997) GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. J Interferon Cytokine Res 17(3):121–134.  https://doi.org/10.1089/jir.1997.17.121PubMedCrossRefGoogle Scholar
  109. 109.
    Michalska A, Blaszczyk K, Wesoly J, Bluyssen HAR (2018) A positive feedback amplifier circuit that regulates interferon (IFN)-stimulated gene expression and controls type I and type II IFN responses. Front Immunol 9:1135.  https://doi.org/10.3389/fimmu.2018.01135PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Gobin SJ, van den Elsen PJ (2000) Transcriptional regulation of the MHC class Ib genes HLA-E, HLA-F, and HLA-G. Hum Immunol 61(11):1102–1107PubMedCrossRefGoogle Scholar
  111. 111.
    Ritter C, Fan K, Paschen A, Reker Hardrup S, Ferrone S, Nghiem P, Ugurel S, Schrama D, Becker JC (2017) Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma. Sci Rep 7(1):2290.  https://doi.org/10.1038/s41598-017-02608-0PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Briere D, Sudhakar N, Woods DM, Hallin J, Engstrom LD, Aranda R, Chiang H, Sodre AL, Olson P, Weber JS, Christensen JG (2018) The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy. Cancer Immunol Immunother 67(3):381–392.  https://doi.org/10.1007/s00262-017-2091-yPubMedCrossRefGoogle Scholar
  113. 113.
    van den Elsen PJ, Holling TM, van der Stoep N, Boss JM (2003) DNA methylation and expression of major histocompatibility complex class I and class II transactivator genes in human developmental tumor cells and in T cell malignancies. Clin Immunol 109(1):46–52PubMedCrossRefGoogle Scholar
  114. 114.
    Vlkova V, Stepanek I, Hruskova V, Senigl F, Mayerova V, Sramek M, Simova J, Bieblova J, Indrova M, Hejhal T, Derian N, Klatzmann D, Six A, Reinis M (2014) Epigenetic regulations in the IFNgamma signalling pathway: IFNgamma-mediated MHC class I upregulation on tumour cells is associated with DNA demethylation of antigen-presenting machinery genes. Oncotarget 5(16):6923–6935.  https://doi.org/10.18632/oncotarget.2222PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Luo N, Nixon MJ, Gonzalez-Ericsson PI, Sanchez V, Opalenik SR, Li H, Zahnow CA, Nickels ML, Liu F, Tantawy MN, Sanders ME, Manning HC, Balko JM (2018) DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer. Nat Commun 9(1):248.  https://doi.org/10.1038/s41467-017-02630-wPubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Kingwell K (2019) Uncoupling resistance to cancer immunotherapy. Nat Rev Drug Discov.  https://doi.org/10.1038/d41573-019-00025-8PubMedCrossRefGoogle Scholar
  117. 117.
    Seliger B (2017) Immune modulatory microRNAs as a novel mechanism to revert immune escape of tumors. Cytokine Growth Factor Rev 36:49–56.  https://doi.org/10.1016/j.cytogfr.2017.07.001PubMedCrossRefGoogle Scholar
  118. 118.
    Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, Sucker A, Hillen U, Foppen MHG, Goldinger SM, Utikal J, Hassel JC, Weide B, Kaehler KC, Loquai C, Mohr P, Gutzmer R, Dummer R, Gabriel S, Wu CJ, Schadendorf D, Garraway LA (2015) Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350(6257):207–211.  https://doi.org/10.1126/science.aad0095PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, Katibah GE, Woo SR, Lemmens E, Banda T, Leong JJ, Metchette K, Dubensky TW Jr, Gajewski TF (2015) Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep 11(7):1018–1030.  https://doi.org/10.1016/j.celrep.2015.04.031PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP (2013) Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med 210(7):1389–1402.  https://doi.org/10.1084/jem.20130066PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Tang H, Qiao J, Fu YX (2016) Immunotherapy and tumor microenvironment. Cancer Lett 370(1):85–90.  https://doi.org/10.1016/j.canlet.2015.10.009PubMedCrossRefGoogle Scholar
  122. 122.
    Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arthur CD, Krebber WJ, Mulder GE, Toebes M, Vesely MD, Lam SS, Korman AJ, Allison JP, Freeman GJ, Sharpe AH, Pearce EL, Schumacher TN, Aebersold R, Rammensee HG, Melief CJ, Mardis ER, Gillanders WE, Artyomov MN, Schreiber RD (2014) Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515(7528):577–581.  https://doi.org/10.1038/nature13988PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Hodi FS (2010) Overcoming immunological tolerance to melanoma: targeting CTLA-4. Asia Pac J Clin Oncol 6(Suppl 1):S16–S23.  https://doi.org/10.1111/j.1743-7563.2010.01271.xPubMedCrossRefGoogle Scholar
  124. 124.
    Redmond WL, Gough MJ, Charbonneau B, Ratliff TL, Weinberg AD (2007) Defects in the acquisition of CD8 T cell effector function after priming with tumor or soluble antigen can be overcome by the addition of an OX40 agonist. J Immunol 179(11):7244–7253PubMedCrossRefGoogle Scholar
  125. 125.
    Rosenberg SA, Restifo NP (2015) Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348(6230):62–68.  https://doi.org/10.1126/science.aaa4967PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Beatty GL, O'Hara M (2016) Chimeric antigen receptor-modified T cells for the treatment of solid tumors: defining the challenges and next steps. Pharmacol Ther 166:30–39.  https://doi.org/10.1016/j.pharmthera.2016.06.010PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Abken H (2017) Driving CARs on the highway to solid cancer: some considerations on the adoptive therapy with CAR T Cells. Hum Gene Ther 28(11):1047–1060.  https://doi.org/10.1089/hum.2017.115PubMedCrossRefGoogle Scholar
  128. 128.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34.  https://doi.org/10.1056/NEJMoa1504030PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Callahan MK, Postow MA, Wolchok JD (2014) CTLA-4 and PD-1 pathway blockade: combinations in the clinic. Front Oncol 4:385.  https://doi.org/10.3389/fonc.2014.00385PubMedCrossRefGoogle Scholar
  130. 130.
    Berrien-Elliott MM, Jackson SR, Meyer JM, Rouskey CJ, Nguyen TL, Yagita H, Greenberg PD, DiPaolo RJ, Teague RM (2013) Durable adoptive immunotherapy for leukemia produced by manipulation of multiple regulatory pathways of CD8+ T-cell tolerance. Cancer Res 73(2):605–616.  https://doi.org/10.1158/0008-5472.CAN-12-2179PubMedCrossRefGoogle Scholar
  131. 131.
    Redmond WL, Linch SN, Kasiewicz MJ (2014) Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity. Cancer Immunol Res 2(2):142–153.  https://doi.org/10.1158/2326-6066.CIR-13-0031-TPubMedCrossRefGoogle Scholar
  132. 132.
    Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF (2014) Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer 2:3.  https://doi.org/10.1186/2051-1426-2-3PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, Hamad L, Kim S, Lacouture ME, LeBoeuf NR, Lenihan D, Onofrei C, Shannon V, Sharma R, Silk AW, Skondra D, Suarez-Almazor ME, Wang Y, Wiley K, Kaufman HL, Ernstoff MS, Society for Immunotherapy of Cancer Toxicity Management Working Group (2017) Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 5(1):95.  https://doi.org/10.1186/s40425-017-0300-zPubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Wilmott JS, Scolyer RA, Long GV, Hersey P (2012) Combined targeted therapy and immunotherapy in the treatment of advanced melanoma. Oncoimmunology 1(6):997–999.  https://doi.org/10.4161/onci.19865PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Comin-Anduix B, Escuin-Ordinas H, Ibarrondo FJ (2016) Tremelimumab: research and clinical development. Onco Targets Ther 9:1767–1776.  https://doi.org/10.2147/OTT.S65802PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Kishton RJ, Sukumar M, Restifo NP (2017) Metabolic regulation of T cell longevity and function in tumor immunotherapy. Cell Metab 26(1):94–109.  https://doi.org/10.1016/j.cmet.2017.06.016PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Chang CH, Pearce EL (2016) Emerging concepts of T cell metabolism as a target of immunotherapy. Nat Immunol 17(4):364–368.  https://doi.org/10.1038/ni.3415PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350(6264):1084–1089.  https://doi.org/10.1126/science.aac4255PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Berard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L (2015) Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350(6264):1079–1084.  https://doi.org/10.1126/science.aad1329PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Conejo-Garcia JR, Rutkowski MR (2015) Small but mighty: selected commensal bacterial species determine the effectiveness of anti-cancer immunotherapies. Immunity 43(6):1037–1039.  https://doi.org/10.1016/j.immuni.2015.11.014PubMedCrossRefGoogle Scholar
  141. 141.
    Jenkins RW, Aref AR, Lizotte PH, Ivanova E, Stinson S, Zhou CW, Bowden M, Deng J, Liu H, Miao D, He MX, Walker W, Zhang G, Tian T, Cheng C, Wei Z, Palakurthi S, Bittinger M, Vitzthum H, Kim JW, Merlino A, Quinn M, Venkataramani C, Kaplan JA, Portell A, Gokhale PC, Phillips B, Smart A, Rotem A, Jones RE, Keogh L, Anguiano M, Stapleton L, Jia Z, Barzily-Rokni M, Canadas I, Thai TC, Hammond MR, Vlahos R, Wang ES, Zhang H, Li S, Hanna GJ, Huang W, Hoang MP, Piris A, Eliane JP, Stemmer-Rachamimov AO, Cameron L, Su MJ, Shah P, Izar B, Thakuria M, LeBoeuf NR, Rabinowits G, Gunda V, Parangi S, Cleary JM, Miller BC, Kitajima S, Thummalapalli R, Miao B, Barbie TU, Sivathanu V, Wong J, Richards WG, Bueno R, Yoon CH, Miret J, Herlyn M, Garraway LA, Van Allen EM, Freeman GJ, Kirschmeier PT, Lorch JH, Ott PA, Hodi FS, Flaherty KT, Kamm RD, Boland GM, Wong KK, Dornan D, Paweletz CP, Barbie DA (2018) Ex vivo profiling of PD-1 blockade using organotypic tumor spheroids. Cancer Discov 8(2):196–215.  https://doi.org/10.1158/2159-8290.CD-17-0833PubMedCrossRefGoogle Scholar
  142. 142.
    Zingg D, Arenas-Ramirez N, Sahin D, Rosalia RA, Antunes AT, Haeusel J, Sommer L, Boyman O (2017) The Histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy. Cell Rep 20(4):854–867.  https://doi.org/10.1016/j.celrep.2017.07.007PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Zheng H, Zhao W, Yan C, Watson CC, Massengill M, Xie M, Massengill C, Noyes DR, Martinez GV, Afzal R, Chen Z, Ren X, Antonia SJ, Haura EB, Ruffell B, Beg AA (2016) HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin Cancer Res 22(16):4119–4132.  https://doi.org/10.1158/1078-0432.CCR-15-2584PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Terranova-Barberio M, Thomas S, Ali N, Pawlowska N, Park J, Krings G, Rosenblum MD, Budillon A, Munster PN (2017) HDAC inhibition potentiates immunotherapy in triple negative breast cancer. Oncotarget 8(69):114156–114172.  https://doi.org/10.18632/oncotarget.23169PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Woods DM, Sodre AL, Villagra A, Sarnaik A, Sotomayor EM, Weber J (2015) HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res 3(12):1375–1385.  https://doi.org/10.1158/2326-6066.CIR-15-0077-TPubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Institute of Medical ImmunologyMartin Luther University Halle-WittenbergHalle (Saale)Germany
  2. 2.Division of Surgical Oncology, Department of Surgery, Massachusetts General HospitalHarvard Medical SchoolBostonUSA

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