S. S. Qin1,2,3, B. Han1,2,3, R. Jewell2,3, K. Jackson2,3, A. C. Chacon2,3, D. C. Linehan2,3,4, S. A. Gerber1,2,3, P. A. Prieto2,3,4 1University Of Rochester School of Medicine and Dentistry,Department Of Microbiology And Immunology,Rochester, NY, USA 2University Of Rochester Medical Center,Center For Tumor Immunology,Rochester, NY, USA 3University of Rochester Medical Center,Department Of Surgery,Rochester, NY, USA 4University of Rochester Medical Center,Wilmot Cancer Institute,Rochester, NY, USA
Introduction:
Despite recent advances in immunotherapy, metastatic melanoma still carries a poor prognosis as only a minority of patients obtain durable responses. Inherent tumor heterogeneity secondary to genomic instability results in distinct immune microenvironments and discordant lesion-specific responses. Interferon-gamma (IFN-γ) is not only a key effector molecule secreted by a functional CD8 T cell response, but is also a crucial molecule in shaping tumor development. In fact, IFN-γ has been associated with both anti-tumorigenic and pro-tumorigenic activities in melanoma by promoting apoptosis of melanoma cells in vitro while increasing aggressiveness of human melanoma cells in vivo. The contribution of IFN-γ to the heterogeneous PD-1 inhibitor response in synchronous metastatic melanoma has yet to be investigated.
Methods:
We generated a murine synchronous metastatic melanoma model to recapitulate human disease using a parental YUMM 1.7 cell line, which contains BrafV600E/Pten-/-/Cdkn2-/- driver mutations, and a UVB-irradiated derivative containing additional de novo somatic mutations, YUMMER 1.7. We characterized the distinct tumor microenvironments via flow cytometry in wildtype and IFN-γ-/- C57BL/6 mice.
Results:
YUMMER and YUMM established separate and distinct tumor microenvironments in the synchronous melanoma model. YUMMER tumor growth and its induced immune response, as measured by stromal MHC I expression and amount of tumor infiltrating CD45+ immune cells, were more IFN-γ sensitive compared to that of YUMM. Despite having increased CD8 immune infiltration (p < 0.01), YUMMER tumors eventually escaped immune surveillance. Furthermore, YUMMER tumors exhibited elevated levels of PD-1+ CD8 T-cell accumulation and of PD-L1+ stromal cells compared to YUMM tumors. This upregulation of PD-1/PD-L1 axis was abolished in IFN-γ-/- mice compared to wildtype mice. Lastly, presence of YUMMER tumors did not increase immune infiltration in YUMM (p > 0.9) tumors nor increase YUMM sensitivity to IFN-γ.
Conclusion:
IFN-γ blunts anti-tumoral CD8 T-cell response via upregulation of PD-1/PD-L1 axis in a murine model of synchronous metastatic melanoma. The presence of an immunogenic tumor does not exert an abscopal effect on a synchronous, but genetically dissimilar, immunogenically “cold” tumor. This suggests that the microenvironments of both tumors individually contribute to the systemic immune response. Genomic and immune characterization of this synchronous model could potentially provide mechanistic insight and explain lesion-specific responses to immunotherapy observed in this challenging patient population.