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Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition

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Abstract

Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy. In 436 patients with metastatic melanoma receiving single line ICI or combination treatment, we tested 25 SNPs, associated with > 2 autoimmune diseases in recent genome-wide association studies, for modulation of ICI efficacy. We found that rs17388568—a risk variant for allergy, colitis and type 1 diabetes—was associated with increased anti-PD-1 response, with significance surpassing multiple testing adjustments (OR 0.26; 95% CI 0.12–0.53; p = 0.0002). This variant maps to a locus of established immune-related genes: IL2 and IL21. Our study provides first evidence that autoimmune genetic susceptibility may modulate ICI efficacy, suggesting that systematic testing of autoimmune risk loci could reveal personalized biomarkers of ICI response.

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Abbreviations

CI:

Confidence interval

GWAS:

Genome-wide association study

ICI:

Immune-checkpoint inhibition

irAEs:

Immune-related adverse events

MGH:

Massachusetts General Hospital

NYULH:

New York University Langone Health

OR:

Odds ratio

PTPN2:

Protein tyrosine phosphatase non-receptor type 2

QC:

Quality control

SNP:

Single nucleotide polymorphism

UCLA:

University of California Los Angeles

References

  1. Society AC (2015) Cancer facts & figure 2015. American Cancer Society, Atlanta

    Google Scholar 

  2. Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM (2011) Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 16(1):5–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, Patt D, Chen T-T, Berman DM, Wolchok JD (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33(17):1889–1894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, Garbe C, Gogas H, Schachter J, Linette G (2013) Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol 31(5):616–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hodi FS, O’day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O’Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16(8):908–918. https://doi.org/10.1016/S1470-2045(15)00083-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16(4):375–384. https://doi.org/10.1016/S1470-2045(15)70076-8

    Article  CAS  PubMed  Google Scholar 

  9. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon R-A, Reed K (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369(2):122–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bertrand A, Kostine M, Truchetet M-E, Schaeverbeke T, Barnetche T (2015) Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med 13(1):211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schindler K, Harmankaya K, Kuk D, Mangana J, Michielin O, Hoeller C, Dummer R, Pehamberger H, Wolchok JD, Postow MA (2014) Correlation of absolute and relative eosinophil counts with immune-related adverse events in melanoma patients treated with ipilimumab. American Society of Clinical Oncology, Alexandria

    Book  Google Scholar 

  13. Tarhini AA, Sander C, Zahoor H, Kirkwood JM, Butterfield LH, Malhotra U, Lin Y (2015) Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma. J Immunother Cancer 3(1):39

    Article  PubMed  PubMed Central  Google Scholar 

  14. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371(23):2189–2199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Carbognin L, Pilotto S, Milella M, Vaccaro V, Brunelli M, Caliò A, Cuppone F, Sperduti I, Giannarelli D, Chilosi M (2015) Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS One 10(6):e0130142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nat 515(7528):568

    Article  CAS  Google Scholar 

  17. Fujisawa Y, Yoshino K, Otsuka A, Funakoshi T, Fujimura T, Yamamoto Y, Hata H, Gosho M, Tanaka R, Yamaguchi K (2017) Fluctuations in routine blood count might signal severe immune-related adverse events in melanoma patients treated with nivolumab. J Dermatol Sci 88(2):225–231

    Article  CAS  PubMed  Google Scholar 

  18. Gopalakrishnan V, Spencer C, Nezi L, Reuben A, Andrews M, Karpinets T, Prieto P, Vicente D, Hoffman K, Wei S (2018) Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359(6371):97–103

    Article  CAS  PubMed  Google Scholar 

  19. Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S, Hansson J, Guida M, Hyams DM, Gómez H, Bastholt L (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 9(1):204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Berman D, Parker SM, Siegel J, Chasalow SD, Weber J, Galbraith S, Targan SR, Wang HL (2010) Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immunity Arch 10(1):11

    Google Scholar 

  21. Breunis WB, Tarazona-Santos E, Chen R, Kiley M, Rosenberg SA, Chanock SJ (2008) Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade. J Immunother (Hagerstown, Md: 1997) 31(6):586

    Article  CAS  Google Scholar 

  22. Queirolo P, Morabito A, Laurent S, Lastraioli S, Piccioli P, Ascierto P, Gentilcore G, Serra M, Marasco A, Tornari E (2013) Association of CTLA-4 polymorphisms with improved overall survival in melanoma patients treated with CTLA-4 blockade: a pilot study. Cancer Invest 31(5):336–345

    Article  CAS  PubMed  Google Scholar 

  23. Attia P, Giao PQ, Michael YJ, Rosenberg SA (2005) Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-CTLA-4. AACR

  24. Hinds DA, McMahon G, Kiefer AK, Do CB, Eriksson N, Evans DM, St Pourcain B, Ring SM, Mountain JL, Francke U (2013) A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci. Nat Genet 45(8):907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, Lee JC, Goyette P, Imielinski M, Latiano A (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43(3):246–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Consortium WTCC (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3000 shared controls. Nature 447(7145):661

    Article  CAS  Google Scholar 

  27. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247

    Article  CAS  PubMed  Google Scholar 

  28. Rendleman J, Vogelsang M, Bapodra A, Adaniel C, Silva I, Moogk D, Martinez CN, Fleming N, Shields J, Shapiro R (2015) Genetic associations of the interleukin locus at 1q32. 1 with clinical outcomes of cutaneous melanoma. J Med Genet 2014:102832

    Google Scholar 

  29. Chistiakov DA, Voronova NV, Chistiakov PA (2008) The crucial role of IL-2/IL-2RA-mediated immune regulation in the pathogenesis of type 1 diabetes, an evidence coming from genetic and animal model studies. Immunol Lett 118(1):1–5

    Article  CAS  PubMed  Google Scholar 

  30. Sim GC, Radvanyi L (2014) The IL-2 cytokine family in cancer immunotherapy. Cytokine Growth Factor Rev 25(4):377–390

    Article  CAS  PubMed  Google Scholar 

  31. Carter LL, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, Collins M, Honjo T, Freeman GJ, Carreno BM (2002) PD-1: PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2. Eur J Immunol 32(3):634–643

    Article  CAS  PubMed  Google Scholar 

  32. Hughes T, Klairmont M, Sharfman WH, Kaufman HL (2015) Interleukin-2, ipilimumab, and anti-PD-1: clinical management and the evolving role of immunotherapy for the treatment of patients with metastatic melanoma. Cancer Biol Ther (just-accepted):00–00

    Article  Google Scholar 

  33. Di Carlo E, De Totero D, Piazza T, Fabbi M, Ferrini S (2007) Role of IL-21 in immune-regulation and tumor immunotherapy. Cancer Immunol Immunother 56(9):1323–1334

    Article  CAS  PubMed  Google Scholar 

  34. Monteleone G, Monteleone I, Fina D, Vavassori P, Blanco GDV, Caruso R, Tersigni R, Alessandroni L, Biancone L, Naccari GC (2005) Interleukin-21 enhances T-helper cell type I signaling and interferon-γ production in Crohn’s disease. Gastroenterology 128(3):687–694

    Article  CAS  PubMed  Google Scholar 

  35. Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, Oukka M, Kuchroo VK (2007) IL-21 initiates an alternative pathway to induce proinflammatory T H 17 cells. Nature 448(7152):484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O’Shea MA, Fauci AS (2008) The common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 181(10):6738–6746

    Article  CAS  PubMed  Google Scholar 

  37. Lewis KE, Selby MJ, Masters G, Valle J, Dito G, Curtis WR, Garcia R, Mink KA, Waggie KS, Holdren MS (2018) Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models. Oncoimmunology 7(1):e1377873

    Article  Google Scholar 

  38. Chow LQM, Gordon MS, Logan TF, Antonia SJ, Bhatia S, Thompson JA, Brahmer JR, Solberg G, Bittner R, Fontana D (2013) Phase I dose escalation study of recombinant interleukin-21 (rIL-21; BMS-982470) in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced or metastatic solid tumors. American Society of Clinical Oncology, Alexandria

    Google Scholar 

  39. Simoncic PD, Lee-Loy A, Barber DL, Tremblay ML, McGlade CJ (2002) The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3. Curr Biol 12(6):446–453

    Article  CAS  PubMed  Google Scholar 

  40. Manguso RT, Pope HW, Zimmer MD, Brown FD, Yates KB, Miller BC, Collins NB, Bi K, LaFleur MW, Juneja VR (2017) In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nat 547(7664):413

    Article  CAS  Google Scholar 

  41. Kugel CH, Douglass SM, Webster MR, Kaur A, Liu Q, Yin X, Weiss SA, Darvishian F, Al-Rohil RN, Ndoye A (2018) Age correlates with response to anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations. Clin Cancer Res 24(21):5347–5356

    Article  PubMed  PubMed Central  Google Scholar 

  42. Conforti F, Pala L, Bagnardi V, De Pas T, Martinetti M, Viale G, Gelber RD, Goldhirsch A (2018) Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol 19(6):737–746

    Article  CAS  PubMed  Google Scholar 

  43. Blank CU, Haanen JB, Ribas A, Schumacher TN (2016) The “cancer immunogram”. Science 352(6286):658–660

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by a Grant from the National Cancer Institute: 1R21CA184432-01.

Author information

Author notes

  1. Vylyny Chat and Robert Ferguson contributed equally to the work.

Authors and Affiliations

  1. Laura and Issac Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, New York, NY, 10016, USA

    Vylyny Chat, Robert Ferguson, Danny Simpson, Esther Kazlow, Rebecca Lax, Una Moran, Iman Osman, Jeffrey Weber & Tomas Kirchhoff

  2. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, USA

    Vylyny Chat, Robert Ferguson, Danny Simpson, Esther Kazlow, Rebecca Lax & Tomas Kirchhoff

  3. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA

    Vylyny Chat, Robert Ferguson, Danny Simpson, Esther Kazlow, Rebecca Lax, Una Moran, Anna Pavlick, Iman Osman, Jeffrey Weber & Tomas Kirchhoff

  4. Department of Medicine, New York University School of Medicine, New York, NY, USA

    Una Moran, Anna Pavlick, Iman Osman & Jeffrey Weber

  5. Ronald O. Perelman, Department of Dermatology, New York University, New York, NY, USA

    Una Moran & Iman Osman

  6. Center for Melanoma, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

    Dennie Frederick, Genevieve Boland, Ryan Sullivan & Keith Flaherty

  7. Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Antoni Ribas

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  1. Vylyny Chat
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Contributions

VC, RF and TK designed the study and drafted the manuscript. VC, RF, EK and RL performed the experiments. VC, RF, DS and TK analyzed the data. UM, AP, DF and GB assisted in sample collections and data curations. RS, AR, KF, IO, JW provided the patient specimens, clinical data and clinical resources. VC, RF, RS, AR, KF, IO, JW and TK edited and revised the manuscript. TK led the project. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Tomas Kirchhoff.

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Conflict of interest

No conflict of interest, except for: Antoni Ribas has received honoraria from consulting with Bristol Myers Squibb, Amgen, Chugai, Genentech, Merck, Novartis and Roche, is in the scientific advisory board of Advaxis, Arcus, Bioncotech, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Merus and Rgenix, during the conduct of this work was in the scientific advisory board and held stock in Kite-Pharma, and is co-founder of PACT Pharma and Tango Therapeutics. Ryan Sullivan serves as a Consultant/Advisory Board member at Merck, Amgen, Compugen, Array Biopharma, Novartis, Roche-Genentech and Replimmune, Syndax, and received research support from Merck, Amgen. Keith Flaherty serves on the Board of Directors of Loxo Oncology, Clovis Oncology, Strata Oncology and Vivid Biosciences; on the Corporate Advisory Boards of X4 Pharmaceuticals and PIC Therapeutics; on the scientific advisory boards of Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Array BioPharma, Shattuck Labs, Arch Oncology, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon Therapeutics, and Tvardi; and as a consultant to Novartis, Genentech, BMS, Merck, Takeda, Verastem, Checkmate, Boston Biomedical, Pierre Fabre, Cell Medica, and Debiopharm. Jeffrey Weber owns stock or other ownership at Altor BioScience, Biond, CytomX Therapeutics, received honoraria from Bristol-Myers Squibb, Merck, Genentech, AbbVie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Amgen, Roche, Ichor Medical Systems, Celldex, CytomX Therapeutics, Nektar, Novartis, Sellas, WindMIL, Takeda, has consulting/advisory role at Celldex, Ichor Medical Systems, Biond, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, AbbVie, Eisai, CytomX Therapeutics, Nektar, Novartis, Sellas, WindMIL, Takeda, and obtained research funding (to the Institution) from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Genentech, Astellas Pharma, Incyte, Roche, Novartis and received funding for travel/accommodations/expenses from Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis, WindMIL, Takeda.

Ethical standards

Written informed consents for the use of the blood specimens and clinical information were obtained at the time of enrollment from all participants and the study was approved by the Institutional Review Board (IRB) at all institutions (NYULH: IRB#10362; MGH/Dana Farber/Harvard Cancer Center: IRB#11–181; UCLA: IRB#11-001918 and 11-003066).

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This work was accepted as a poster presentation at the ASCO annual meeting (American Society of Clinical Oncology) from June 1–5, 2018 in Chicago, IL, USA.

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Chat, V., Ferguson, R., Simpson, D. et al. Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition. Cancer Immunol Immunother 68, 897–905 (2019). https://doi.org/10.1007/s00262-019-02318-8

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