Cancer Immunology, Immunotherapy

, Volume 60, Issue 3, pp 433–442 | Cite as

Immunologic biomarkers as correlates of clinical response to cancer immunotherapy

Focussed Research Review

Abstract

Over the last few years, several newly developed immune-based cancer therapies have been shown to induce clinical responses in significant numbers of patients. As a result, there is a need to identify immune biomarkers capable of predicting clinical response. If there were laboratory parameters that could define patients with improved disease outcomes after immunomodulation, product development would accelerate, optimization of existing immune-based treatments would be facilitated and patient selection for specific interventions might be optimized. Although there are no validated cancer immunologic biomarkers that are predictive of clinical response currently in widespread use, there is much published literature that has informed investigators as to which markers may be the most promising. Population-based studies of endogenous tumor immune infiltrates and gene expression analyses have identified specific cell populations and phenotypes of immune cells that are most likely to mediate anti-tumor immunity. Further, clinical trials of cancer vaccines and other cancer directed immunotherapy have identified candidate immunologic biomarkers that are statistically associated with beneficial clinical outcomes after immune-based cancer therapies. Biomarkers that measure the magnitude of the Type I immune response generated with immune therapy, epitope spreading, and autoimmunity are readily detected in the peripheral blood and, in clinical trials of cancer immunotherapy, have been associated with response to treatment.

Keywords

Immunity Biomarkers T cell Clinical response Correlation Immunotherapy 

Abbreviations

ADCC

Antibody-dependent cell-mediated cytotoxicity

APC

Antigen-presenting cells

CI

Confidence interval

CTLA-4

Cytotoxic T-lymphocyte antigen 4

DFS

Disease-free survival

DTH

Delayed type hypersensitivity

GM-CSF

Granulocyte macrophage colony stimulating factor

HER2

HER-2/neu

HPV

Human papilloma virus

HR

Hazard ratio

IFN

Interferon

IL

Interleukin

KLH

Keyhole limpet hemocyanin

NCI

National Cancer Institute

NK

Natural killer

OS

Overall survival

PDL

Programmed death ligand

PSA

Prostate-specific antigen

RR

Relative risk

SNP

Single nucleotide polymorphisms

TGF

Transforming growth factor

References

  1. 1.
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363(5):411–422CrossRefPubMedGoogle Scholar
  2. 2.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723CrossRefPubMedGoogle Scholar
  3. 3.
    Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK et al (2010) Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363(14):1324–1334CrossRefPubMedGoogle Scholar
  4. 4.
    Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP (2009) Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med 206(8):1717–1725CrossRefPubMedGoogle Scholar
  5. 5.
    Subramanian J, Simon R (2010) What should physicians look for in evaluating prognostic gene-expression signatures? Nat Rev Clin Oncol 7(6):327–334CrossRefPubMedGoogle Scholar
  6. 6.
    Reyal F, van Vliet MH, Armstrong NJ, Horlings HM, de Visser KE, Kok M, Teschendorff AE, Mook S, van ‘t Veer L, Caldas C et al (2008) A comprehensive analysis of prognostic signatures reveals the high predictive capacity of the proliferation immune response and RNA splicing modules in breast cancer. Br Cancer Res 10(6):R93CrossRefGoogle Scholar
  7. 7.
    Staaf J, Ringner M, Vallon-Christersson J, Jonsson G, Bendahl PO, Holm K, Arason A, Gunnarsson H, Hegardt C, Agnarsson BA et al (2010) Identification of subtypes in human epidermal growth factor receptor 2–positive breast cancer reveals a gene signature prognostic of outcome. J Clin Oncol 28(11):1813–1820CrossRefPubMedGoogle Scholar
  8. 8.
    Teschendorff AE, Miremadi A, Pinder SE, Ellis IO, Caldas C (2007) An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol 8(8):R157CrossRefPubMedGoogle Scholar
  9. 9.
    Yamshchikov GV, Mullins DW, Chang CC, Ogino T, Thompson L, Presley J, Galavotti H, Aquila W, Deacon D, Ross W et al (2005) Sequential immune escape and shifting of T cell responses in a long-term survivor of melanoma. J Immunol 174(11):6863–6871PubMedGoogle Scholar
  10. 10.
    Mandruzzato S, Callegaro A, Turcatel G, Francescato S, Montesco MC, Chiarion-Sileni V, Mocellin S, Rossi CR, Bicciato S, Wang E et al (2006) A gene expression signature associated with survival in metastatic melanoma. J Transl Med 4:50CrossRefPubMedGoogle Scholar
  11. 11.
    Bogunovic D, O’Neill DW, Belitskaya-Levy I, Vacic V, Yu YL, Adams S, Darvishian F, Berman R, Shapiro R, Pavlick AC et al (2009) Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival. Proc Natl Acad Sci USA 106(48):20429–20434CrossRefPubMedGoogle Scholar
  12. 12.
    Roepman P, Jassem J, Smit EF, Muley T, Niklinski J, van de Velde T, Witteveen AT, Rzyman W, Floore A, Burgers S et al (2009) An immune response enriched 72-gene prognostic profile for early-stage non-small-cell lung cancer. Clin Cancer Res 15(1):284–290CrossRefPubMedGoogle Scholar
  13. 13.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964CrossRefPubMedGoogle Scholar
  14. 14.
    Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN et al (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348(3):203–213CrossRefPubMedGoogle Scholar
  15. 15.
    Kondratiev S, Sabo E, Yakirevich E, Lavie O, Resnick MB et al (2004) Intratumoral CD8+ T lymphocytes as a prognostic factor of survival in endometrial carcinoma. Clin Cancer Res 10(13):4450–4456CrossRefPubMedGoogle Scholar
  16. 16.
    Ladanyi A, Kiss J, Somlai B, Gilde K, Fejos Z, Mohos A, Gaudi I, Timar J (2007) Density of DC-LAMP(+) mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol Immunother 56(9):1459–1469CrossRefPubMedGoogle Scholar
  17. 17.
    Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, Suzuki Y, Shintaku I, Nagura H, Ohtani H (2001) Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 61(13):5132–5136PubMedGoogle Scholar
  18. 18.
    Oshikiri T, Miyamoto M, Shichinohe T, Suzuoki M, Hiraoka K, Nakakubo Y, Shinohara T, Itoh T, Kondo S, Katoh H (2003) Prognostic value of intratumoral CD8+ T lymphocyte in extrahepatic bile duct carcinoma as essential immune response. J Surg Oncol 84(4):224–228CrossRefPubMedGoogle Scholar
  19. 19.
    Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 27(35):5944–5951CrossRefPubMedGoogle Scholar
  20. 20.
    Schumacher K, Haensch W, Roefzaad C, Schlag PM (2001) Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res 61(10):3932–3936PubMedGoogle Scholar
  21. 21.
    Sinicrope FA, Rego RL, Ansell SM, Knutson KL, Foster NR, Sargent DJ (2009) Intraepithelial effector (CD3+)/regulatory (FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma. Gastroenterology 137(4):1270–1279CrossRefPubMedGoogle Scholar
  22. 22.
    Yamada N, Oizumi S, Kikuchi E, Shinagawa N, Konishi-Sakakibara J, Ishimine A, Aoe K, Gemba K, Kishimoto T, Torigoe T et al (2010) CD8 +tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother 59(10):1543–1549CrossRefPubMedGoogle Scholar
  23. 23.
    Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353(25):2654–2666CrossRefPubMedGoogle Scholar
  24. 24.
    Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, Banham AH (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24(34):5373–5380CrossRefPubMedGoogle Scholar
  25. 25.
    Ladoire S, Arnould L, Apetoh L, Coudert B, Martin F, Chauffert B, Fumoleau P, Ghiringhelli F (2008) Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells. Clin Cancer Res 14(8):2413–2420CrossRefPubMedGoogle Scholar
  26. 26.
    Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, Santarlasci V, Serni S, Cosmi L, Maggi L et al. 2010 Frequency of regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma. BJU Int. doi:10.1111/j.1464-410X.2010.09555.x
  27. 27.
    Shen Z, Zhou S, Wang Y, Li RL, Zhong C, Liang C, Sun Y (2010) Higher intratumoral infiltrated Foxp3 + Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer. J Cancer Res Clin Oncol 136(10):1585–1595CrossRefPubMedGoogle Scholar
  28. 28.
    Shimizu K, Nakata M, Hirami Y, Yukawa T, Maeda A, Tanemoto K (2010) Tumor-infiltrating Foxp3+ regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancer. J Thorac Oncol 5(5):585–590PubMedGoogle Scholar
  29. 29.
    Lee NR, Song EK, Jang KY, Choi HN, Moon WS, Kwon K, Lee JH, Yim CY, Kwak JY (2008) Prognostic impact of tumor infiltrating FOXP3 positive regulatory T cells in diffuse large B-cell lymphoma at diagnosis. Leuk Lymphoma 49(2):247–256CrossRefPubMedGoogle Scholar
  30. 30.
    Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27(2):186–192CrossRefPubMedGoogle Scholar
  31. 31.
    Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S (2007) Overexpression of B7–H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 56(8):1173–1182CrossRefPubMedGoogle Scholar
  32. 32.
    Thompson RH, Dong H, Kwon ED (2007) Implications of B7–H1 expression in clear cell carcinoma of the kidney for prognostication and therapy. Clin Cancer Res 13(2 Pt 2):709s–715sCrossRefPubMedGoogle Scholar
  33. 33.
    Mizukami Y, Kono K, Maruyama T, Watanabe M, Kawaguchi Y, Kamimura K, Fujii H (2008) Downregulation of HLA Class I molecules in the tumour is associated with a poor prognosis in patients with oesophageal squamous cell carcinoma. Br J Cancer 99(9):1462–1467CrossRefPubMedGoogle Scholar
  34. 34.
    Ogino T, Shigyo H, Ishii H, Katayama A, Miyokawa N, Harabuchi Y, Ferrone S (2006) HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res 66(18):9281–9289CrossRefPubMedGoogle Scholar
  35. 35.
    Desruisseau S, Palmari J, Giusti C, Romain S, Martin PM, Berthois Y (2006) Determination of TGFbeta1 protein level in human primary breast cancers and its relationship with survival. Br J Cancer 94(2):239–246CrossRefPubMedGoogle Scholar
  36. 36.
    Disis ML (2010) Immune regulation of cancer. J Clin Oncol 28(29):4531–4538CrossRefPubMedGoogle Scholar
  37. 37.
    Slingluff CL Jr, Petroni GR, Chianese-Bullock KA, Smolkin ME, Hibbitts S, Murphy C, Johansen N, Grosh WW, Yamshchikov GV, Neese PY et al (2007) Immunologic and clinical outcomes of a randomized phase II trial of two multipeptide vaccines for melanoma in the adjuvant setting. Clin Cancer Res 13(21):6386–6395CrossRefPubMedGoogle Scholar
  38. 38.
    Kirkwood JM, Lee S, Moschos SJ, Albertini MR, Michalak JC, Sander C, Whiteside T, Butterfield LH, Weiner L (2009) Immunogenicity and antitumor effects of vaccination with peptide vaccine ± granulocyte-monocyte colony-stimulating factor and/or IFN-alpha2b in advanced metastatic melanoma: eastern cooperative oncology group phase II Trial E1696. Clin Cancer Res 15(4):1443–1451CrossRefPubMedGoogle Scholar
  39. 39.
    Gulley JL, Arlen PM, Madan RA, Tsang KY, Pazdur MP, Skarupa L, Jones JL, Poole DJ, Higgins JP, Hodge JW et al (2010) Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother 59(5):663–674CrossRefPubMedGoogle Scholar
  40. 40.
    Disis ML, Wallace DR, Gooley TA, Dang Y, Slota M, Lu H, Coveler AL, Childs JS, Higgins DM, Fintak PA et al (2009) Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. J Clin Oncol 27(28):4685–4692CrossRefPubMedGoogle Scholar
  41. 41.
    Barth RJ Jr, Fischer DA, Wallace PK, Channon JY, Noelle R, Gui J, Ernstoff MS (2010) A randomized trial of ex vivo CD40L activation of a DC vaccine in colorectal cancer patients: tumor-specific immune responses are associated with improved survival. Clin Cancer Res 16(22):5548–5556Google Scholar
  42. 42.
    Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, Essahsah F, Fathers LM, Offringa R, Drijfhout JW et al (2009) Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med 361(19):1838–1847CrossRefPubMedGoogle Scholar
  43. 43.
    Disis ML, Schiffman K, Gooley TA, McNeel DG, Rinn K, Knutson KL (2000) Delayed-type hypersensitivity response is a predictor of peripheral blood T-cell immunity after HER-2/neu peptide immunization. Clin Cancer Res 6(4):1347–1350PubMedGoogle Scholar
  44. 44.
    Baars A, Claessen AM, van den Eertwegh AJ, Gall HE, Stam AG, Meijer S, Giaccone G, Meijer CJ, Scheper RJ, Wagstaff J et al (2000) Skin tests predict survival after autologous tumor cell vaccination in metastatic melanoma: experience in 81 patients. Ann Oncol 11(8):965–970CrossRefPubMedGoogle Scholar
  45. 45.
    Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, Goemann M, Coleman J, Grochow L, Donehower RC (2001) Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 19(1):145–156PubMedGoogle Scholar
  46. 46.
    Lopez MN, Pereda C, Segal G, Munoz L, Aguilera R, Gonzalez FE, Escobar A, Ginesta A, Reyes D, Gonzalez R (2009) Prolonged survival of dendritic cell-vaccinated melanoma patients correlates with tumor-specific delayed type IV hypersensitivity response and reduction of tumor growth factor beta-expressing T cells. J Clin Oncol 27(6):945–952CrossRefPubMedGoogle Scholar
  47. 47.
    de Vries IJ, Bernsen MR, Lesterhuis WJ, Scharenborg NM, Strijk SP, Gerritsen MJ, Ruiter DJ, Figdor CG, Punt CJ, Adema GJ (2005) Immunomonitoring tumor-specific T cells in delayed-type hypersensitivity skin biopsies after dendritic cell vaccination correlates with clinical outcome. J Clin Oncol 23(24):5779–5787CrossRefPubMedGoogle Scholar
  48. 48.
    Butterfield LH, Ribas A, Dissette VB, Amarnani SN, Vu HT, Oseguera D, Wang HJ, Elashoff RM, McBride WH, Mukherji B et al (2003) Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma. Clin Cancer Res 9(3):998–1008PubMedGoogle Scholar
  49. 49.
    Wierecky J, Muller MR, Wirths S, Halder-Oehler E, Dorfel D, Schmidt SM, Hantschel M, Brugger W, Schroder S, Horger MS et al (2006) Immunologic and clinical responses after vaccinations with peptide-pulsed dendritic cells in metastatic renal cancer patients. Cancer Res 66(11):5910–5918CrossRefPubMedGoogle Scholar
  50. 50.
    Disis ML, Gooley TA, Rinn K, Davis D, Piepkorn M, Cheever MA, Knutson KL, Schiffman K (2002) Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol 20(11):2624–2632CrossRefPubMedGoogle Scholar
  51. 51.
    Salazar LG, Goodell V, O’Meara M et al (2009) Persistent immunity and survival after immunization with a HER-2/neu vaccine. J Clin Oncol (Meeting Abstracts) 27(15S):2010Google Scholar
  52. 52.
    Quaglino P, Marenco F, Osella-Abate S, Cappello N, Ortoncelli M, Salomone B, Fierro MT, Savoia P, Bernengo MG (2010) Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study. Ann Oncol 21(2):409–414CrossRefPubMedGoogle Scholar
  53. 53.
    Phan GQ, Attia P, Steinberg SM, White DE, Rosenberg SA (2001) Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 19(15):3477–3482PubMedGoogle Scholar
  54. 54.
    Beck KE, Blansfield JA, Tran KQ, Feldman AL, Hughes MS, Royal RE, Kammula US, Topalian SL, Sherry RM, Kleiner D et al (2006) Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 24(15):2283–2289CrossRefPubMedGoogle Scholar
  55. 55.
    Gogas H, Ioannovich J, Dafni U, Stavropoulou-Giokas C, Frangia K, Tsoutsos D, Panagiotou P, Polyzos A, Papadopoulos O, Stratigos A (2006) Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354(7):709–718CrossRefPubMedGoogle Scholar
  56. 56.
    Bouwhuis MG, Suciu S, Collette S, Aamdal S, Kruit WH, Bastholt L, Stierner U, Sales F, Patel P, Punt CJ (2009) Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon. J Natl Cancer Inst 101(12):869–877CrossRefPubMedGoogle Scholar
  57. 57.
    Sittler T, Zhou J, Park J, Yuen NK, Sarantopoulos S, Mollick J, Salgia R, Giobbie-Hurder A, Dranoff G, Hodi FS (2008) Concerted potent humoral immune responses to autoantigens are associated with tumor destruction and favorable clinical outcomes without autoimmunity. Clin Cancer Res 14(12):3896–3905CrossRefPubMedGoogle Scholar
  58. 58.
    Hartmann TB, Bazhin AV, Schadendorf D, Eichmuller SB (2005) SEREX identification of new tumor antigens linked to melanoma-associated retinopathy. Int J Cancer 114(1):88–93CrossRefPubMedGoogle Scholar
  59. 59.
    Di Rosa F, Pabst R (2005) The bone marrow: a nest for migratory memory T cells. Trends Immunol 26(7):360–366CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Tumor Vaccine Group, Center for Translational Medicine in Women’s HealthUniversity of WashingtonSeattleUSA

Personalised recommendations