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Critical role of PD-L1 expression on non-tumor cells rather than on tumor cells for effective anti-PD-L1 immunotherapy in a transplantable mouse hematopoietic tumor model

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Abstract

The expression of PD-L1 on tumor cells or within the tumor microenvironment has been associated with good prognosis and sustained clinical responses in immunotherapeutic regimens based on PD-L1/PD-1/CD80 immune checkpoint blockade. To look into the current controversy in cancer immunotherapy of the relative importance of PD-L1 expression on tumor cells versus non-tumor cells of the tumor microenvironment, a hematological mouse tumor model was chosen. By combining a genetic CRISPR/Cas9 and immunotherapeutic approach and using a syngeneic hematopoietic transplantable tumor model (E.G7-cOVA tumor cells), we demonstrated that dual blockade of PD-L1 interaction with PD-1 and CD80 enhanced anti-tumor immune responses that either delayed tumor growth or led to its complete eradication. PD-L1 expression on non-tumor cells of the tumor microenvironment was required for the promotion of tumor immune escape and its blockade elicited potent anti-tumor responses to PD-L1 WT and to PD-L1-deficient tumor cells. PD-L1+ tumors implanted in PD-L1-deficient mice exhibited delayed tumor growth independently of PD-L1 blockade. These findings emphasize that PD-L1 expression on non-tumor cells plays a major role in this tumor model. These observations should turn our attention to the tumor microenvironment in hematological malignancies because of its unappreciated contribution to create a conditioned niche for the tumor to grow and evade the anti-tumor immune response.

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Abbreviations

APC:

Antigen-presenting cells

ATCC:

American Type Culture Collection

CD:

Cluster of differentiation

CTLA-4:

Cytotoxic T-lymphocyte antigen 4

FCS:

Fetal calf serum

ICB:

Immune checkpoint blockade

mAb:

Monoclonal antibody

MHC:

Major histocompatibility complex

NK:

Natural killer

PCR:

Polymerase chain reaction

PD-1:

Programmed death-1

PD-L1:

Programmed death-ligand 1

PI:

Propidium iodide

pLNs:

Peripheral lymph nodes

SD:

Standard deviation

SEM:

Standard error of the mean

SFM:

Serum-free medium

TCR:

T cell receptor

References

  1. Ribatti D (2017) The concept of immune surveillance against tumors. The first theories. Oncotarget 8(4):7175–7180. https://doi.org/10.18632/oncotarget.12739

    Article  PubMed  Google Scholar 

  2. Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21(2):137–148. https://doi.org/10.1016/j.immuni.2004.07.017

    Article  CAS  PubMed  Google Scholar 

  3. Finn OJ (2018) A believer’s overview of cancer immunosurveillance and immunotherapy. J Immunol (Baltimore, Md : 1950) 200(2):385–391. https://doi.org/10.4049/jimmunol.1701302

    Article  CAS  Google Scholar 

  4. De Plaen E, Lurquin C, Van Pel A, Mariame B, Szikora JP, Wolfel T, Sibille C, Chomez P, Boon T (1988) Immunogenic (tum-) variants of mouse tumor P815: cloning of the gene of tum-antigen P91A and identification of the tum-mutation. Proc Natl Acad Sci USA 85(7):2274–2278

    Article  PubMed  PubMed Central  Google Scholar 

  5. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science (New York, NY) 254(5038):1643–1647

    Article  Google Scholar 

  6. Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH (2016) Coinhibitory Pathways in Immunotherapy for Cancer. Annu Rev Immunol 34:539–573. https://doi.org/10.1146/annurev-immunol-032414-112049

    Article  CAS  PubMed  Google Scholar 

  7. Nicholas NS, Apollonio B (1863) Ramsay AG (2016) Tumor microenvironment (TME)-driven immune suppression in B cell malignancy. Biochem Biophys Acta 3:471–482. https://doi.org/10.1016/j.bbamcr.2015.11.003

    Article  CAS  Google Scholar 

  8. Curran EK, Godfrey J, Kline J (2017) Mechanisms of immune tolerance in leukemia and lymphoma. Trends Immunol 38(7):513–525. https://doi.org/10.1016/j.it.2017.04.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Upadhyay R, Hammerich L, Peng P, Brown B, Merad M, Brody JD (2015) Lymphoma: immune evasion strategies. Cancers 7(2):736–762. https://doi.org/10.3390/cancers7020736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P (1987) A new member of the immunoglobulin superfamily—CTLA-4. Nature 328(6127):267–270. https://doi.org/10.1038/328267a0

    Article  CAS  PubMed  Google Scholar 

  11. Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science (New York, NY) 271(5256):1734–1736

    Article  CAS  Google Scholar 

  12. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 99(19):12293–12297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chikuma S, Terawaki S, Hayashi T, Nabeshima R, Yoshida T, Shibayama S, Okazaki T, Honjo T (2009) PD-1-mediated suppression of IL-2 production induces CD8 + T cell anergy in vivo. J Immunol (Baltimore, Md : 1950) 182(11):6682–6689. https://doi.org/10.4049/jimmunol.0900080

    Article  CAS  Google Scholar 

  14. Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11(11):3887–3895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science (New York, NY) 291(5502):319–322

    Article  CAS  Google Scholar 

  16. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7):1027–1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2(3):261–268

    Article  CAS  PubMed  Google Scholar 

  18. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (2007) Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27(1):111–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8(8):793–800

    Article  CAS  PubMed  Google Scholar 

  20. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571. https://doi.org/10.1038/nature13954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. https://doi.org/10.1038/nrc3239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gajewski TF, Louahed J, Brichard VG (2010) Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J (Sudbury, Mass) 16(4):399–403. https://doi.org/10.1097/PPO.0b013e3181eacbd8

    Article  CAS  Google Scholar 

  23. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF (2013) Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 5(200):200ra116. https://doi.org/10.1126/scitranslmed.3006504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Juneja VR, McGuire KA, Manguso RT, LaFleur MW, Collins N, Haining WN, Freeman GJ, Sharpe AH (2017) PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 214(4):895–904. https://doi.org/10.1084/jem.20160801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wherry EJ, Kurachi M (2015) Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 15(8):486–499. https://doi.org/10.1038/nri3862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. De Sousa Linhares A, Leitner J, Grabmeier-Pfistershammer K, Steinberger P (2018) Not all immune checkpoints are created equal. Front Immunol 9:1909. https://doi.org/10.3389/fimmu.2018.01909

    Article  CAS  Google Scholar 

  27. Chihara N, Madi A, Kondo T, Zhang H, Acharya N, Singer M, Nyman J, Marjanovic ND, Kowalczyk MS, Wang C, Kurtulus S, Law T, Etminan Y, Nevin J, Buckley CD, Burkett PR, Buenrostro JD, Rozenblatt-Rosen O, Anderson AC, Regev A, Kuchroo VK (2018) Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558(7710):454–459. https://doi.org/10.1038/s41586-018-0206-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Anderson AC, Joller N, Kuchroo VK (2016) Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44(5):989–1004. https://doi.org/10.1016/j.immuni.2016.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Murray PJ, Smale ST (2012) Restraint of inflammatory signaling by interdependent strata of negative regulatory pathways. Nat Immunol 13(10):916–924. https://doi.org/10.1038/ni.2391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Annibali O, Crescenzi A, Tomarchio V, Pagano A, Bianchi A, Grifoni A, Avvisati G (2018) PD-1/PD-L1 checkpoint in hematological malignancies. Leuk Res 67:45–55. https://doi.org/10.1016/j.leukres.2018.01.014

    Article  CAS  PubMed  Google Scholar 

  31. Wilcox RA, Feldman AL, Wada DA, Yang ZZ, Comfere NI, Dong H, Kwon ED, Novak AJ, Markovic SN, Pittelkow MR, Witzig TE, Ansell SM (2009) B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood 114(10):2149–2158. https://doi.org/10.1182/blood-2009-04-216671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Carbone FR, Moore MW, Sheil JM, Bevan MJ (1988) Induction of cytotoxic T lymphocytes by primary in vitro stimulation with peptides. J Exp Med 167(6):1767–1779

    Article  CAS  PubMed  Google Scholar 

  33. Young L, Sung J, Stacey G, Masters JR (2010) Detection of Mycoplasma in cell cultures. Nat Protoc 5(5):929–934. https://doi.org/10.1038/nprot.2010.43

    Article  CAS  PubMed  Google Scholar 

  34. Sanjana NE, Shalem O, Zhang F (2014) Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods 11(8):783–784. https://doi.org/10.1038/nmeth.3047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tsushima F, Iwai H, Otsuki N, Abe M, Hirose S, Yamazaki T, Akiba H, Yagita H, Takahashi Y, Omura K, Okumura K, Azuma M (2003) Preferential contribution of B7-H1 to programmed death-1-mediated regulation of hapten-specific allergic inflammatory responses. Eur J Immunol 33(10):2773–2782

    Article  CAS  PubMed  Google Scholar 

  36. Unkeless JC (1979) Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors. J Exp Med 150(3):580–596

    Article  CAS  PubMed  Google Scholar 

  37. Nelson DJ, Mukherjee S, Bundell C, Fisher S, van Hagen D, Robinson B (2001) Tumor progression despite efficient tumor antigen cross-presentation and effective “arming” of tumor antigen-specific CTL. J Immunol (Baltimore, Md : 1950) 166(9):5557–5566. https://doi.org/10.4049/jimmunol.166.9.5557

    Article  CAS  Google Scholar 

  38. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8(11):2281–2308. https://doi.org/10.1038/nprot.2013.143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tang F, Zheng P (2018) Tumor cells versus host immune cells: whose PD-L1 contributes to PD-1/PD-L1 blockade mediated cancer immunotherapy? Cell Biosci 8:34. https://doi.org/10.1186/s13578-018-0232-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lin H, Wei S, Hurt EM, Green MD, Zhao L, Vatan L, Szeliga W, Herbst R, Harms PW, Fecher LA, Vats P, Chinnaiyan AM, Lao CD, Lawrence TS, Wicha M, Hamanishi J, Mandai M, Kryczek I, Zou W (2018) Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J Clin Investig 128(2):805–815. https://doi.org/10.1172/jci96113

    Article  PubMed  PubMed Central  Google Scholar 

  41. Teng MW, Ngiow SF, Ribas A, Smyth MJ (2015) Classifying cancers based on T-cell Infiltration and PD-L1. Can Res 75(11):2139–2145. https://doi.org/10.1158/0008-5472.can-15-0255

    Article  CAS  Google Scholar 

  42. Noguchi T, Ward JP, Gubin MM, Arthur CD, Lee SH, Hundal J, Selby MJ, Graziano RF, Mardis ER, Korman AJ, Schreiber RD (2017) Temporally distinct PD-L1 expression by tumor and host cells contributes to immune escape. Cancer Immunol Res 5(2):106–117. https://doi.org/10.1158/2326-6066.cir-16-0391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kleinovink JW, Marijt KA, Schoonderwoerd MJA, van Hall T, Ossendorp F, Fransen MF (2017) PD-L1 expression on malignant cells is no prerequisite for checkpoint therapy. Oncoimmunology 6(4):e1294299. https://doi.org/10.1080/2162402x.2017.1294299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang X, Cheng C, Hou J, Qi X, Wang X, Han P, Yang X (2019) Distinct contribution of PD-L1 suppression by spatial expression of PD-L1 on tumor and non-tumor cells. Cell Mol Immunol 16(4):392–400. https://doi.org/10.1038/s41423-018-0021-3

    Article  CAS  PubMed  Google Scholar 

  45. Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B, Adamow M, Kuk D, Panageas KS, Carrera C, Wong P, Quagliarello F, Wubbenhorst B, D’Andrea K, Pauken KE, Herati RS, Staupe RP, Schenkel JM, McGettigan S, Kothari S, George SM, Vonderheide RH, Amaravadi RK, Karakousis GC, Schuchter LM, Xu X, Nathanson KL, Wolchok JD, Gangadhar TC, Wherry EJ (2017) T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545(7652):60–65. https://doi.org/10.1038/nature22079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Umezu D, Okada N, Sakoda Y, Adachi K, Ojima T, Yamaue H, Eto M, Tamada K (2019) Inhibitory functions of PD-L1 and PD-L2 in the regulation of anti-tumor immunity in murine tumor microenvironment. Cancer Immunol Immunother 68(2):201–211. https://doi.org/10.1007/s00262-018-2263-4

    Article  CAS  PubMed  Google Scholar 

  47. Tang H, Liang Y, Anders RA, Taube JM, Qiu X, Mulgaonkar A, Liu X, Harrington SM, Guo J, Xin Y, Xiong Y, Nham K, Silvers W, Hao G, Sun X, Chen M, Hannan R, Qiao J, Dong H, Peng H, Fu YX (2018) PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J Clin Investig 128(2):580–588. https://doi.org/10.1172/jci96061

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lau J, Cheung J, Navarro A, Lianoglou S, Haley B, Totpal K, Sanders L, Koeppen H, Caplazi P, McBride J, Chiu H, Hong R, Grogan J, Javinal V, Yauch R, Irving B, Belvin M, Mellman I, Kim JM, Schmidt M (2017) Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice. Nat Commun 8:14572. https://doi.org/10.1038/ncomms14572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shi L, Chen S, Yang L, Li Y (2013) The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol 6(1):74. https://doi.org/10.1186/1756-8722-6-74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sugiura D, Maruhashi T, Okazaki IM, Shimizu K, Maeda TK, Takemoto T, Okazaki T (2019) Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science (New York, NY) 364(6440):558–566. https://doi.org/10.1126/science.aav7062

    Article  CAS  Google Scholar 

  51. Held W, Mariuzza RA (2011) Cis-trans interactions of cell surface receptors: biological roles and structural basis. Cell Mol Life Sci 68(21):3469–3478. https://doi.org/10.1007/s00018-011-0798-z

    Article  CAS  PubMed  Google Scholar 

  52. Chaudhri A, Xiao Y, Klee AN, Wang X, Zhu B, Freeman GJ (2018) PD-L1 binds to B7-1 only in cis on the same cell surface. Cancer Immunol Res 6(8):921–929. https://doi.org/10.1158/2326-6066.cir-17-0316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhao Y, Lee CK, Lin CH, Gassen RB, Xu X, Huang Z, Xiao C, Bonorino C, Lu LF, Bui JD, Hui E (2019) PD-L1:CD80 cis-heterodimer triggers the co-stimulatory receptor CD28 while repressing the inhibitory PD-1 and CTLA-4 pathways. Immunity 51(6):1059e1059–1073e1059. https://doi.org/10.1016/j.immuni.2019.11.003

    Article  CAS  Google Scholar 

  54. Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, Shan Q, Hale JS, Lee J, Nasti TH, Sharpe AH, Freeman GJ, Germain RN, Nakaya HI, Xue HH, Ahmed R (2016) Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537(7620):417–421. https://doi.org/10.1038/nature19330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ikemizu S, Gilbert RJ, Fennelly JA, Collins AV, Harlos K, Jones EY, Stuart DI, Davis SJ (2000) Structure and dimerization of a soluble form of B7-1. Immunity 12(1):51–60. https://doi.org/10.1016/s1074-7613(00)80158-2

    Article  CAS  PubMed  Google Scholar 

  56. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, Baker J, Jeffery LE, Kaur S, Briggs Z, Hou TZ, Futter CE, Anderson G, Walker LS, Sansom DM (2011) Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science (New York, NY) 332(6029):600–603. https://doi.org/10.1126/science.1202947

    Article  CAS  Google Scholar 

  57. Mojica FJ, Diez-Villasenor C, Garcia-Martinez J, Soria E (2005) Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements. J Mol Evol 60(2):174–182. https://doi.org/10.1007/s00239-004-0046-3

    Article  CAS  PubMed  Google Scholar 

  58. Doudna JA, Charpentier E (2014) Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science (New York, NY) 346(6213):1258096. https://doi.org/10.1126/science.1258096

    Article  CAS  Google Scholar 

  59. Ajina R, Zamalin D, Zuo A, Moussa M, Catalfamo M, Jablonski SA, Weiner LM (2019) SpCas9-expression by tumor cells can cause T cell-dependent tumor rejection in immunocompetent mice. Oncoimmunology 8(5):e1577127. https://doi.org/10.1080/2162402x.2019.1577127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Burnet FM (1970) The concept of immunological surveillance. Prog Exp Tumor Res 13:1–27

    Article  CAS  PubMed  Google Scholar 

  61. Thomas L (1982) On immunosurveillance in human cancer. Yale J Biol Med 55(3–4):329–333

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Xiong H, Mittman S, Rodriguez R, Pacheco-Sanchez P, Moskalenko M, Yang Y, Elstrott J, Ritter AT, Muller S, Nickles D, Arenzana TL, Capietto AH, Delamarre L, Modrusan Z, Rutz S, Mellman I, Cubas R (2019) Coexpression of inhibitory receptors enriches for activated and functional CD8(+) T cells in murine syngeneic tumor models. Cancer Immunol Res. https://doi.org/10.1158/2326-6066.cir-18-0750

    Article  PubMed  Google Scholar 

  63. Moore MW, Carbone FR, Bevan MJ (1988) Introduction of soluble protein into the class I pathway of antigen processing and presentation. Cell 54(6):777–785

    Article  CAS  PubMed  Google Scholar 

  64. Dranoff G (2012) Experimental mouse tumour models: what can be learnt about human cancer immunology? Nat Rev Immunol 12(1):61–66. https://doi.org/10.1038/nri3129

    Article  CAS  Google Scholar 

  65. Dong H, Zhu G, Tamada K, Flies DB, van Deursen JM, Chen L (2004) B7-H1 determines accumulation and deletion of intrahepatic CD8(+) T lymphocytes. Immunity 20(3):327–336. https://doi.org/10.1016/s1074-7613(04)00050-0

    Article  CAS  PubMed  Google Scholar 

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Funding

This work has been supported by Grant FIS PI# 1300029 (Fondo de Investigaciones Sanitarias, Ministry of Health, Spanish Government, and co-funded by European Union ERDF/ESF, “Investing in your future”), LE093U13 and Unit of Excellence Research UIC #012 (Department of Education of the Regional Government, Junta de Castilla y Leon) and Gerencia Regional de Salud (BIO/01/15) to JIRB. It was also funded by Miguel Servet National Grant (Health National Organization Research) CP12/03063, CPII17/00002 and FIS PI16/00002 (Instituto de Salud Carlos III and co-funded by European Union ERDF/ESF, “Investing in your future”), and Gerencia Regional de Salud GRS963/A/2014, GRS1142/A/2015 and GRS 1505/A/2017 to M.L.R.G. This work has been partially funded by the National Network CIBER-ONC (oncology research) CB16/12/00480.

Author information

Authors and Affiliations

  1. Transplantation Immunobiology Section, Institute of Molecular Biology, Proteomics and Genomics, University of Leon, Campus de Vegazana s/n, 24071, León, Spain

    Jose-Ignacio Rodriguez-Barbosa & Maria-Luisa del Rio

  2. Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan

    Miyuki Azuma

  3. Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, 45147, Germany

    Gennadiy Zelinskyy

  4. Department of Hematology, University Hospital Virgen del Rocio/Institute of Biomedicine (IBIS/CSIC/CIBERONC), Seville, 41013, Spain

    Jose-Antonio Perez-Simon

  5. Castilla and Leon Regional Transplantation Coordination, Leon University Hospital, Altos de Nava s/n, 24007, León, Spain

    Maria-Luisa del Rio

Authors
  1. Jose-Ignacio Rodriguez-Barbosa
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  2. Miyuki Azuma
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  3. Gennadiy Zelinskyy
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  4. Jose-Antonio Perez-Simon
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  5. Maria-Luisa del Rio
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Contributions

Jose-Ignacio Rodriguez-Barbosa and Maria-Luisa del Rio conceived the working hypothesis, performed the experiments, analyzed data and wrote the manuscript. Miyuki Azuma and JA Perez-Simon contributed with reagents, comments and suggestions. Gennadiy Zelinskyy made the in vivo experiments using PD-L1-deficient mice. All authors discussed the results, provided critical input and contributed to the final manuscript.

Corresponding authors

Correspondence to Jose-Ignacio Rodriguez-Barbosa or Maria-Luisa del Rio.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The Animal Welfare Committee of the University of Alcala de Henares (Madrid) in accordance with the European Guidelines for Animal Care and Use of Laboratory Animals approved all experiments with rodents (authorization # OH-UAH-2016/015).

Animal source

Eight- to 12-week-old female C57BL-6 J (B6, from Janvier Labs) and C57BL/6-Tg (TcraTcrb)1100Mjb/J (also known as OT-I mice) were used in this work. OT-I transgenic mice exhibit a rearranged TCR that recognizes OVA residues 257–264, SIINFEKL peptide in the context of H-2b [63]. These mice were kindly provided by Dr. David Sancho (CNIC, National Center for Cardiovascular Disease, Madrid). B6-background PD-L1−/− (B7-H1-KO) mice were originally generated by Lieping Chen [65].

Cell line authentication

The EL-4 cell line is a chemically induced lymphoma cell line from C57BL/6 mice. E.G7 is a transplantable cell line derived from EL-4 thymoma cells that were transfected with a plasmid carrying a cytoplasmic version of chicken ovalbumin (OVA). Both cell lines were kindly provided by Prof. Dr. Ignacio Melero (CIMA, Navarra, Spain), who obtained them from ATCC. No cell line authentication was necessary.

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Rodriguez-Barbosa, JI., Azuma, M., Zelinskyy, G. et al. Critical role of PD-L1 expression on non-tumor cells rather than on tumor cells for effective anti-PD-L1 immunotherapy in a transplantable mouse hematopoietic tumor model. Cancer Immunol Immunother 69, 1001–1014 (2020). https://doi.org/10.1007/s00262-020-02520-z

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