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Immune Pathways Combine to Refine Response

  • Immune balance is maintained through the combination of activating and inhibitory signaling pathways1,2
    • Inhibitory pathways can act as safety switches to quickly turn off an immune response3,4
    • Inhibition through these pathways can therefore limit the effectiveness of activating signals5
    • Immune pathways work in combination to regulate the 3 key stages of the immune response: presentation, infiltration, and elimination6

Diagram of immune response to signaling pathways along with NK cell, effector T-cell, and non-effector cell mechanisms


Targets are listed by primary mechanisms. Secondary mechanisms may exist.

  • The immune response is a self-propagating and continuous process. Presentation, infiltration, and elimination are modulated by distinct immune pathways that can function simultaneously or in sequence7-10
  • These pathways serve the following two roles in regulating the immune response:
    • Influence the breadth and magnitude of subsequent stages
    • Balance activation and inhibition at each stage
  • Once an immune response is initiated, each stage can potentiate or limit the activity of subsequent stages
    • Inhibition of antigen presentation limits the number of activated cytotoxic T cells that infiltrate the tumor and eliminate tumor cells11
      • This inhibition can be further perpetuated by inhibitory signals functioning at the tumor-cell elimination stage12,13
    • Conversely, activating pathways that promote antigen presentation and immune-cell infiltration may amplify tumor-cell elimination3
  • Preclinical data suggest that modulation of 2 or more immune pathways can more efficiently activate immune activity, leading to an inflamed tumor, compared with either pathway alone28-32
  • At Bristol-Myers Squibb, ongoing research aims to further our understanding of how signaling pathways interact and to identify combination strategies, such as inhibition of multiple pathways, that may activate an effective immune response

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REFERENCES–Immune pathways combine to refine response

1. Leung J, Suh WK. The CD28-B7 family in anti-tumor immunity: emerging concepts in cancer immunotherapy. Immune Netw. 2014;14(6):265-276. 2. Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Ann Rev Immunol. 2013;31:227-258. 3. Watzl C, Stebbins CC, Long EO. Cutting edge: NK cell inhibitory receptors prevent tyrosine phosphorylation of the activation receptor 2B4 (CD244). J Immunol. 2000;165(7):3545-3548. 4. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 5. Stark S, Watzl C. 2B4 (CD244), NTB-A and CRACC (CS1) stimulate cytotoxicity but no proliferation in human NK cells. Int Immunol. 2006;18(2):241-247. 6. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1-10. 7. Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1(5):405-413. 8. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682-687. 9. Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DAA. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol. 2004;172(9):5450-5455. 10. Campbell KS, Purdy AK. Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology. 2011;132(3):315-325. 11. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492-1504. 12. Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543-9553. 13. Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol. 2013;94(1):25-39. 14. Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci Transl Med. 2013; 5(200):200ra116. 15. Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114:1537-1544. 16. Harlin H, Meng Y, Peterson AC, et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69(7):3077-3085. 17. Lee SJ, Myers L, Muralimohan G, et al. 4-1BB and OX40 dual costimulation synergistically stimulate primary specific CD8 T cells for robust effector function. J Immunol. 2004;173(5):3002-3012. 18. Bryceson YT, March ME, Ljunggren H-G, Long EO. Activation, co-activation, and co-stimulation of resting human NK cells. Immunol Rev. 2006;214:73-91. 19. Antonia SJ, Larkin J, Ascierto PA. Immuno-oncology combinations: a review of clinical experience and future prospects. Clin Cancer Res. 2014;20(24):6258-6268. 20. Cruz-Munoz ME, Dong Z, Shi X, Zhang S, Veillette A. Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function. Nat Immunol. 2009;10(3):297-305. 21. Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271-275. 22. Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204(6):1257-1265. 23. Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol. 2014. doi:10.1101/cshperspect.a021857. 24. Fallarino F, Grohmann U, You S, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells. J Immunol. 2006;176(11):6752-6761. 25. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49-61. 26. Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest. 2015;125(9):3356-3364. 27. Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Clin Cancer Res. 2014;74(18):5057-5069. 28. Chen S, Lee LF, Fisher TS, et al. Combination of 4-1BB agonist and PD-1 antagonist promotes antitumor effector/memory CD8 T cells in a poorly immunogenic tumor model. Cancer Immunol Res. 2014;3(2):149-160. 29. Lu L, Xu X, Zhang B, Zhang R, Ji H, Wang X. Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs. J Transl Med. 2014. doi:10.1186/1479-5876-12-36. 30. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275-4280. 31. Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2011;72(4):917-927. 32. Singh M, Vianden C, Cantwell MJ, et al. Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain. Nat Commun. 2017;8(1):1447.