Abstract 1605: "Reverse abscopal effect": Immunologically cold tumors alter systemic immunity and confer PD-1 resistance to immunologically hot tumors in synchronous melanoma
Authors: Qin Shuyang S. , Han Booyeon J. , Chacon Alexander C. , Melucci Alexa D. , Williams Alyssa R. , Jewell Rachel , Kim Minsoo , Linehan David C. , Gerber Scott A. , Prieto Peter A. 
Published: June 2022

Abstract
PD-1 (programmed cell death protein-1) blockade, an immunotherapy that re-stimulates antitumor CD8 T cell response, has revolutionized the treatment of metastatic melanoma. However, the majority of melanoma patients eventually acquire therapy resistance. The emergence of resistant metastases likely results from de novo somatic mutations secondary to inherent tumor genetic instability. We hypothesize that intertumoral genetic differences introduce immunosuppressive mechanisms, such as inducing myeloid-derived suppressor cell differentiation, that dampen existing antitumor immune responses. As all metastases share one host immune system, we investigated the local and systemic effects of intertumoral heterogeneity on antitumor immunity and PD-1 immunotherapy response in mice with multiple, synchronous melanoma metastases. To recapitulate intertumoral heterogeneity, we simultaneously injected PD-1 blockade-resistant YUMM 1.7 and its UVB-irradiated, PD-1 sensitive, derivative YUMMER 1.7 melanoma cell lines into opposite flanks of the same C57BL/6J mouse. We previously demonstrated that tumor-specific de novo somatic mutations, in combination with the host immune response, generate distinct microenvironments in synchronous YUMMER (immunologically active) and YUMM (immunologically inactive) tumors. Our novel murine synchronous melanoma model demonstrated that the presence of immunologically inactive YUMM tumors changes systemic antitumor immunity, including the induction of host splenic myelopoiesis. This phenomenon is accompanied by an increase in YUMMER intratumoral M-CSF (macrophage colony stimulating factor) concentration and an influx of immunosuppressive PD-L1+ (PD-1 ligand) macrophages into YUMMER tumors as assessed by flow cytometry and Luminex analyses. Furthermore, compared to control CD8 T cells, synchronous YUMMER-infiltrating CD8 T cells exhibit reduced functionality, with increased surface PD-1 persistence and failure to respond to PD-1 blockade. As a result, the presence of YUMM tumors are able to confer PD-1 blockade resistance to the normally PD-1 sensitive YUMMER tumors. Our results suggest that intertumoral heterogeneity leads to a “reverse abscopal effect,” where immunologically “cold” tumors can alter systemic myeloid immune responses to suppress antitumor CD8 T cell function in immunologically “hot” tumors. As such, the addition of myeloid-altering agents to PD-1 immunotherapy are likely to improve treatment efficacy and prevent acquired therapy resistance in patients with metastatic melanoma.
Citation Format: Shuyang S. Qin, Booyeon J. Han, Alexander C. Chacon, Alexa D. Melucci, Alyssa R. Williams, Rachel Jewell, Minsoo Kim, David C. Linehan, Scott A. Gerber, Peter A. Prieto. "Reverse abscopal effect": Immunologically cold tumors alter systemic immunity and confer PD-1 resistance to immunologically hot tumors in synchronous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1605.