Overcoming immunotherapy resistance in melanoma defective of IFN-g signaling

Melanoma loss of IFN-g signaling is a major mechanism of resistance to immune checkpoint blockers such as anti-CTLA-4 and anti-PD-1, a prominent type of immunotherapies offering unprecedented therapeutic hopes to melanoma patients. However, strategies of overcoming this resistance have been elusive.
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Melanoma was claimed largely incurable prior to the era of immune checkpoint blockers (ICBs).  By antagonizing negative signals emanated from immune checkpoints (CTLA-4, PD-1, and PD-L1) that suppress T cell-mediated anti-tumor immune responses, ICBs (i.e., anti-CTLA and anti-PD-1/L1) rejuvenate the effector function of tumor-infiltrating T cells (TILs) [1-4], leading to tumor eradication and impressive therapeutic outcomes [5, 6]. Over the past 11 years or so, more than 70 approvals have been granted to ICBs in a multitude of cancer types [7], some of which are for first-line use, propelling ICBs to a major pillar of cancer care. However, therapeutic resistance to ICBs is common. Accumulative data indicate that only a subset of melanoma patients benefit from ICBs, limiting their clinical utility. 

To understand why the majority of melanoma patients are not responsive to ICBs, initial efforts from many groups, including us (together with Dr. Pam Sharma and Jim Allison) [8-12], identify loss of IFN-γ signaling in melanoma cells as a major mechanism of resistance to ICB. Despite this major finding, strategies of overcoming this resistance have remained largely unexplored. Furthermore, given the pivotal role of T cells in orchestrating therapeutic effects of ICBs, limited information is available on how melanoma-intrinsic IFN-γ signaling impacts TILs. To tackle these issues and fill in the knowledge gaps, we generated a syngeneic melanoma model defective of IFN-γ signaling and completely resistant to ICBs (IFNγR1KO) [13]. Interestingly, we found that IFNγR1KO melanomas have reduced abundance of CD8+ TILs at the baseline and lack anti-CTLA-4-induced infiltration and functional rejuvenation of TILs. Similarly, reduced expression of T cell signature genes was observed in human melanomas with impaired IFN-γ signaling. Additional multi-omics studies informed an aberrantly activated mTOR-JAK1/2 axis in IFNγR1KO melanoma cells. Importantly, targeting this axis with an FDA-approved JAK inhibitor, Ruxolitinib (Ruxo) selectively suppressed IFNγR1KO but not scrambled control melanoma, indicating that Ruxo can serve as a “targeted” therapy for ICB-resistant IFNγR1KO melanoma. In-depth mechanistic analyses showed that Ruxo mediates its therapeutic effects by reprogramming TILs but not through direct killing of tumor cells. Consequently, depletion of T cells and host TNF signaling completely abrogated Ruxo efficacy. Taken together, our study reported that disruption of IFN-γ signaling in tumor cells renders TILs colder and activates the mTOR-JAK1/2 axis, which, when targeted with Ruxo, reprograms TILs and selectively suppressed the growth of IFNγR1KO melanoma (Fig. 1).

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In conclusion, since Ruxo is clinically approved and being tested in patients with advanced solid tumors (NCT02646748), non-small cell lung cancer (NCT02917993), and triple-negative breast cancer (NCT02876302) [14], our study justifies further testing of Ruxo in patients with advanced melanoma that are resistant to ICBs, particularly those with impaired IFN-γ signaling. We are actively soliciting clinical interests in exploring JAK1/2 inhibition as a strategy to overcome ICB resistance in melanoma patients, a pressing unmet medical need.

References

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2          Peggs KS, Quezada SA, Korman AJ, et al. Principles and use of anti-ctla4 antibody in human cancer immunotherapy. Curr Opin Immunol 2006;18:206-213.

3          Simpson TR, Li F, Montalvo-Ortiz W, et al. Fc-dependent depletion of tumor-infiltrating regulatory t cells co-defines the efficacy of anti-ctla-4 therapy against melanoma. J Exp Med 2013;210:1695-1710.

4          Shi LZ, Fu T, Guan B, et al. Interdependent il-7 and ifn-gamma signalling in t-cell controls tumour eradication by combined alpha-ctla-4+alpha-pd-1 therapy. Nat Commun 2016;7:12335.

5          Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-723.

6          Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-133.

7          Shen H, Yang ES-H, Conry M, et al. Predictive biomarkers for immune checkpoint blockade and opportunities for combination therapies. Genes & Diseases 2019

8          Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to pd-1 blockade in melanoma. N Engl J Med 2016;375:819-829.

9          Patel SJ, Sanjana NE, Kishton RJ, et al. Identification of essential genes for cancer immunotherapy. Nature 2017;548:537-542.

10        Pan D, Kobayashi A, Jiang P, et al. A major chromatin regulator determines resistance of tumor cells to t cell-mediated killing. Science 2018;359:770-775.

11        Manguso RT, Pope HW, Zimmer MD, et al. In vivo crispr screening identifies ptpn2 as a cancer immunotherapy target. Nature 2017;547:413-418.

12        Gao J*, Shi LZ*, Zhao H*, et al. Loss of ifn-gamma pathway genes in tumor cells as a mechanism of resistance to anti-ctla-4 therapy. Cell 2016;167:397-404 e399. (*: first authors)

13        Shen H, Huang F, Zhang X, et al. Selective suppression of melanoma lacking ifn-γ pathway by jak inhibition depends on t cells and host tnf signaling. Nat Commun 2022;13:5013.

14        Hammaren HM, Virtanen AT, Raivola J, et al. The regulation of jaks in cytokine signaling and its breakdown in disease. Cytokine 2019;118:48-63.

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