Immune Pathways Combine to Refine Response

Signaling pathways work in combination to refine
the immune response

Immune balance is maintained through the combination of activating and inhibitory signaling pathways^1,2

Inhibitory pathways can act as safety switches to quickly turn off an immune response^3,4
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

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 sequence^7-10
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 stage^12,13

Conversely, activating pathways that promote antigen presentation and immune-cell infiltration may amplify tumor-cell elimination³

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Activating and inhibitory pathways combine to maintain immune balance

Specific activating and inhibitory receptors are present within each stage of the immune response

Because these stages are inherently different, a pathway that regulates antigen presentation may have a different function than one that modulates tumor-cell elimination^3,4,12

Tumors can evade the immune response by amplifying inhibitory pathways or suppressing activating pathways, leading to a noninflamed (cold) tumor^14-16
The way in which activating and inhibitory pathways function together determines the continuation or attenuation of the immune response

Activating pathways can synergistically or additively enhance T- or natural killer
(NK)-cell activity^17,18
In contrast, the presence of multiple inhibitory pathways, including immune checkpoint pathways, can amplify the opportunities for tumor cells to evade the immune response¹⁹

Inhibition through these pathways can therefore limit the effectiveness of activating signals⁵

When inhibitory and activating signals are both present, the ability to enhance effector-cell activity can depend on the scope and strength of inhibition⁵

Inhibitory pathways that act on effector cells can directly modulate antitumor activity^3,4,9,20
Inhibitory pathways that act on non-effector cells (eg, regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells) support cancer growth by suppressing effector-cell activity,^6,21-26 but may not completely block immune activity²⁷

They can, however, extend the inhibitory potential of checkpoint pathways

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Modulating immune pathways in combination may enhance
the immune response

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 alone^28-32
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

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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. 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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.