Cancer Immunology, Immunotherapy

, Volume 61, Issue 7, pp 1019–1031 | Cite as

An immune-active tumor microenvironment favors clinical response to ipilimumab

  • Rui-Ru Ji
  • Scott D. Chasalow
  • Lisu Wang
  • Omid Hamid
  • Henrik Schmidt
  • John Cogswell
  • Suresh Alaparthy
  • David Berman
  • Maria Jure-Kunkel
  • Nathan O. Siemers
  • Jeffrey R. Jackson
  • Vafa Shahabi
Original article

Abstract

Purpose

Ipilimumab, a fully human monoclonal antibody specific to CTLA-4, has been shown to improve overall survival in metastatic melanoma patients. As a consequence of CTLA-4 blockade, ipilimumab treatment is associated with proliferation and activation of peripheral T cells. To better understand various tumor-associated components that may influence the clinical outcome of ipilimumab treatment, gene expression profiles of tumors from patients treated with ipilimumab were characterized.

Experimental design

Gene expression profiling was performed on tumor biopsies collected from 45 melanoma patients before and 3 weeks after the start of treatment in a phase II clinical trial.

Results

Analysis of pre-treatment tumors indicated that patients with high baseline expression levels of immune-related genes were more likely to respond favorably to ipilimumab. Furthermore, ipilimumab appeared to induce two major changes in tumors from patients who exhibited clinical activity: genes involved in immune response showed increased expression, whereas expression of genes for melanoma-specific antigens and genes involved in cell proliferation decreased. These changes were associated with the total lymphocyte infiltrate in tumors, and there was a suggestion of association with prolonged overall survival in these patients. Many IFN-γ-inducible genes and Th1-associated markers showed increased expression after ipilimumab treatment, suggesting an accumulation of this particular type of T cell at the tumor sites, which might play an important role in mediating the antitumor activity of ipilimumab.

Conclusions

These results support the proposed mechanism of action of ipilimumab, suggesting that cell-mediated immune responses play an important role in the antitumor activity of ipilimumab.

Keywords

Ipilimumab Metastatic melanoma Cytotoxic T lymphocyte antigen-4 Gene expression profiling Immunotherapy 

Supplementary material

262_2011_1172_MOESM1_ESM.xlsx (2.7 mb)
Supplementary material 1 (XLSX 2754 kb)
262_2011_1172_MOESM2_ESM.pptx (1.3 mb)
Supplementary material 2 (PPTX 1373 kb)

References

  1. 1.
    American Cancer Society (2009) Cancer facts and figures 2009. http://www.cancer.org/acs/groups/content/@nho/documents/document/500809webpdf.pdf
  2. 2.
    Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK (eds). SEER Cancer Statistics Review, 1975–2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011
  3. 3.
    Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C et al (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985, 1993. J Clin Oncol 17(7):2105–2116PubMedGoogle Scholar
  4. 4.
    Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D et al (2011) Improved survival with vemurafenib in melanoma with braf v600e mutation. N Engl J Med 364(26):2507–2516PubMedCrossRefGoogle Scholar
  5. 5.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723PubMedCrossRefGoogle Scholar
  6. 6.
    Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok J (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526Google Scholar
  7. 7.
    Steer HJ, Lake RA, Nowak AK, Robinson BW (2010) Harnessing the immune response to treat cancer. Oncogene 29(48):6301–6313PubMedCrossRefGoogle Scholar
  8. 8.
    Chambers CA, Kuhns MS, Egen JG, Allison JP (2001) Ctla-4-mediated inhibition in regulation of t cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 19:565–594PubMedCrossRefGoogle Scholar
  9. 9.
    Murillo O, Arina A, Hervas-Stubbs S, Gupta A, McCluskey B, Dubrot J, Palazon A, Azpilikueta A, Ochoa MC, Alfaro C, Solano S et al (2008) Therapeutic antitumor efficacy of anti-cd137 agonistic monoclonal antibody in mouse models of myeloma. Clin Cancer Res 14(21):6895–6906PubMedCrossRefGoogle Scholar
  10. 10.
    Chen H, Liakou CI, Kamat A, Pettaway C, Ward JF, Tang DN, Sun J, Jungbluth AA, Troncoso P, Logothetis C, Sharma P (2009) Anti-ctla-4 therapy results in higher cd4+ ICOShi t cell frequency and IFN-gamma levels in both nonmalignant and malignant prostate tissues. Proceedings of the National Academy of Sciences of the United States of America 106(8):2729–2734Google Scholar
  11. 11.
    Chambers CA, Krummel MF, Boitel B, Hurwitz A, Sullivan TJ, Fournier S, Cassell D, Brunner M, Allison JP (1996) The role of ctla-4 in the regulation and initiation of t-cell responses. Immunol Rev 153:27–46PubMedCrossRefGoogle Scholar
  12. 12.
    Tarhini AA, Iqbal F (2010) CTLA-4 blockade: Therapeutic potential in cancer treatments. OncoTarg Ther 3:15–25Google Scholar
  13. 13.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723Google Scholar
  14. 14.
    Harlin H, Kuna TV, Peterson AC, Meng Y, Gajewski TF (2006) Tumor progression despite massive influx of activated cd8(+) t cells in a patient with malignant melanoma ascites. Cancer Immunol Immunother 55(10):1185–1197PubMedCrossRefGoogle Scholar
  15. 15.
    Kunz M, Toksoy A, Goebeler M, Engelhardt E, Brocker E, Gillitzer R (1999) Strong expression of the lymphoattractant c-x-c chemokine mig is associated with heavy infiltration of t cells in human malignant melanoma. J Pathol 189(4):552–558PubMedCrossRefGoogle Scholar
  16. 16.
    Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S, Hansson J, Guida M, Hyams DM, Gomez H, Bastholt L, Chasalow SD, Berman D (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Trans Med 9:204Google Scholar
  17. 17.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481Google Scholar
  18. 18.
    Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, Macrae S, Nelson M, Canning C, Lowy I, Korman A et al (2008) Immunologic and clinical effects of antibody blockade of cytotoxic t lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proceedings of the National Academy of Sciences of the United States of America 105(8):3005–3010Google Scholar
  19. 19.
    Cole KE, Strick CA, Paradis TJ, Ogborne KT, Loetscher M, Gladue RP, Lin W, Boyd JG, Moser B, Wood DE, Sahagan BG et al (1998) Interferon-inducible t cell alpha chemoattractant (i-tac): A novel non-elr cxc chemokine with potent activity on activated t cells through selective high affinity binding to cxcr3. J Exp Med 187(12):2009–2021PubMedCrossRefGoogle Scholar
  20. 20.
    Liao F, Alkhatib G, Peden KW, Sharma G, Berger EA, Farber JM (1997) Strl33, a novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and t cell line-tropic HIV-1. J Exp Med 185(11):2015–2023PubMedCrossRefGoogle Scholar
  21. 21.
    Du X, Poltorak A, Wei Y, Beutler B (2000) Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur Cytokine Netw 11(3):362–371PubMedGoogle Scholar
  22. 22.
    Gorska MM, Stafford SJ, Cen O, Sur S, Alam R (2004) Unc119, a novel activator of lck/fyn, is essential for t cell activation. J Exp Med 199(3):369–379PubMedCrossRefGoogle Scholar
  23. 23.
    Mavoungou E, Georges-Courbot MC, Poaty-Mavoungou V, Nguyen HT, Yaba P, Delicat A, Georges AJ, Russo-Marie F (1997) HIV and SIV envelope glycoproteins induce phospholipase A2 activation in human and macaque lymphocytes. J Acquir Immune Defic Syndr Hum Retrovirol 16(1):1–9PubMedCrossRefGoogle Scholar
  24. 24.
    Laabi Y, Gras MP, Carbonnel F, Brouet JC, Berger R, Larsen CJ, Tsapis A (1992) A new gene, bcm, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant t cell lymphoma. EMBO J 11(11):3897–3904PubMedGoogle Scholar
  25. 25.
    Tomlinson IM, Cook GP, Walter G, Carter NP, Riethman H, Buluwela L, Rabbitts TH, Winter G (1995) A complete map of the human immunoglobulin vh locus. Ann NY Acad Sci 764:43–46PubMedCrossRefGoogle Scholar
  26. 26.
    Crouser ED, Culver DA, Knox KS, Julian MW, Shao G, Abraham S, Liyanarachchi S, Macre JE, Wewers MD, Gavrilin MA, Ross P et al (2009) Gene expression profiling identifies mmp-12 and adamdec1 as potential pathogenic mediators of pulmonary sarcoidosis. Am J Respir Crit Care Med 179(10):929–938PubMedCrossRefGoogle Scholar
  27. 27.
    Bakos RM, Maier T, Besch R, Mestel DS, Ruzicka T, Sturm RA, Berking C Nestin and sox9 and sox10 transcription factors are coexpressed in melanoma. Exp Dermatol 19(8):e89–e94Google Scholar
  28. 28.
    Yasumoto K, Yokoyama K, Shibata K, Tomita Y, Shibahara S (1994) Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene. Mol Cell Biol 14(12):8058–8070PubMedGoogle Scholar
  29. 29.
    Hearing VJ (1973) Mammalian melanogenesis: tyrosinase versus peroxidase involvement, and activation mechanisms. Arch Biochem Biophys 158(2):720–725PubMedCrossRefGoogle Scholar
  30. 30.
    Cheah MS, Wallace CD, Hoffman RM (1984) Hypomethylation of DNA in human cancer cells: a site-specific change in the c-myc oncogene. J Natl Cancer Inst 73(5):1057–1065PubMedGoogle Scholar
  31. 31.
    Rao UN, Bakker A, Swalsky PA, Finkelstein SD (1999) Max interacting protein 1: loss of heterozygosity is frequent in desmoplastic melanoma. Mod Pathol 12(4):344–350PubMedGoogle Scholar
  32. 32.
    Furlanetto RW, Harwell SE, Baggs RB (1993) Effects of insulin-like growth factor receptor inhibition on human melanomas in culture and in athymic mice. Cancer Res 53(11):2522–2526PubMedGoogle Scholar
  33. 33.
    Rieber M, Rieber MS (1994) Cyclin-dependent kinase 2 and cyclin a interaction with e2f are targets for tyrosine induction of b16 melanoma terminal differentiation. Cell Growth Differ 5(12):1339–1346PubMedGoogle Scholar
  34. 34.
    Draetta GF (1994) Mammalian g1 cyclins. Curr Opin Cell Biol 6(6):842–846PubMedCrossRefGoogle Scholar
  35. 35.
    Schmollinger JC, Vonderheide RH, Hoar KM, Maecker B, Schultze JL, Hodi FS, Soiffer RJ, Jung K, Kuroda MJ, Letvin NL, Greenfield EA et al (2003) Melanoma inhibitor of apoptosis protein (ml-iap) is a target for immune-mediated tumor destruction. Proceedings of the National Academy of Sciences of the United States of America 100(6):3398–3403Google Scholar
  36. 36.
    Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ (1998) Intracellular regulation of trail-induced apoptosis in human melanoma cells. J Immunol 161(6):2833–2840PubMedGoogle Scholar
  37. 37.
    Chen YT, Gure AO, Tsang S, Stockert E, Jager E, Knuth A, Old LJ (1998) Identification of multiple cancer/testis antigens by allogeneic antibody screening of a melanoma cell line library. Proceedings of the National Academy of Sciences of the United States of America 95(12):6919–6923Google Scholar
  38. 38.
    Parmiani G (2001) Melanoma antigens and their recognition by t cells. Keio J Med 50(2):86–90PubMedCrossRefGoogle Scholar
  39. 39.
    Schoenborn JR, Wilson CB (2007) Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41–101PubMedCrossRefGoogle Scholar
  40. 40.
    Zeng W, Miyazato A, Chen G, Kajigaya S, Young NS, Maciejewski JP (2006) Interferon-gamma-induced gene expression in cd34 cells: Identification of pathologic cytokine-specific signature profiles. Blood 107(1):167–175PubMedCrossRefGoogle Scholar
  41. 41.
    Bosco A, McKenna KL, Devitt CJ, Firth MJ, Sly PD, Holt PG (2006) Identification of novel th2-associated genes in t memory responses to allergens. J Immunol 176(8):4766–4777PubMedGoogle Scholar
  42. 42.
    Narayanan S, Silva R, Peruzzi G, Alvarez Y, Simhadri VR, Debell K, Coligan JE, Borrego F (2010) Human th1 cells that express cd300a are polyfunctional and after stimulation up-regulate the t-box transcription factor eomesodermin. PLoS One 5(5):e10636PubMedCrossRefGoogle Scholar
  43. 43.
    Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pages F, Galon J (2011) Clinical impact of different classes of infiltrating t cytotoxic and helper cells (th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 71(4):1263–1271PubMedCrossRefGoogle Scholar
  44. 44.
    Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF (2009) Chemokine expression in melanoma metastases associated with cd8+ t-cell recruitment. Cancer Res 69(7):3077–3085PubMedCrossRefGoogle Scholar
  45. 45.
    Kalinski P, Mailliard RB, Giermasz A, Zeh HJ, Basse P, Bartlett DL, Kirkwood JM, Lotze MT, Herberman RB (2005) Natural killer-dendritic cell cross-talk in cancer immunotherapy. Expert Opin Biol Ther 5(10):1303–1315PubMedCrossRefGoogle Scholar
  46. 46.
    Yuan J, Gnjatic S, Li H, Powel S, Gallardo HF, Ritter E, Ku GY, Jungbluth AA, Segal NH, Rasalan TS, Manukian G et al (2008) Ctla-4 blockade enhances polyfunctional ny-eso-1 specific t cell responses in metastatic melanoma patients with clinical benefit. Proceedings of the National Academy of Sciences of the United States of America 105(51):20410–20415Google Scholar
  47. 47.
    Ebrahimnejad A, Streichert T, Nollau P, Horst AK, Wagener C, Bamberger AM, Brummer J (2004) Ceacam1 enhances invasion and migration of melanocytic and melanoma cells. Am J Pathol 165(5):1781–1787PubMedCrossRefGoogle Scholar
  48. 48.
    Winnepenninckx V, Lazar V, Michiels S, Dessen P, Stas M, Alonso SR, Avril MF, Ortiz Romero PL, Robert T, Balacescu O, Eggermont AM et al (2006) Gene expression profiling of primary cutaneous melanoma and clinical outcome. J Natl Cancer Inst 98(7):472–482PubMedCrossRefGoogle Scholar
  49. 49.
    Bogunovic D, O’Neill DW, Belitskaya-Levy I, Vacic V, Yu YL, Adams S, Darvishian F, Berman R, Shapiro R, Pavlick AC, Lonardi S et al (2009) Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival. Proceedings of the National Academy of Sciences of the United States of America 106(48):20429–20434Google Scholar
  50. 50.
    Ascierto ML, Kmieciak M, Idowu MO, Manjili R, Zhao Y, Grimes M, Dumur C, Wang E, Ramakrishnan V, Wang XY, Bear HD et al (2011) A signature of immune function genes associated with recurrence-free survival in breast cancer patients. Breast Cancer Res TreatGoogle Scholar
  51. 51.
    Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Rui-Ru Ji
    • 1
  • Scott D. Chasalow
    • 1
  • Lisu Wang
    • 1
  • Omid Hamid
    • 2
  • Henrik Schmidt
    • 3
  • John Cogswell
    • 1
  • Suresh Alaparthy
    • 1
  • David Berman
    • 1
  • Maria Jure-Kunkel
    • 1
  • Nathan O. Siemers
    • 1
  • Jeffrey R. Jackson
    • 1
  • Vafa Shahabi
    • 1
  1. 1.Bristol-Myers Squibb CompanyPrincetonUSA
  2. 2.The Angeles Clinic and Research InstituteSanta MonicaUSA
  3. 3.Aarhus University HospitalAarhusDenmark

Personalised recommendations