Pathology of B cell and neutrophil infiltration in the YUMMER1.7 mouse model of spontaneous melanoma tumor regression

Abstract

Abstract We evaluated the spontaneous and immunotherapy-induced histological changes in the tumor microenvironment of a mouse melanoma regression model consisting of C57BL/6J mice implanted with syngeneic YUMMER1.7 melanoma cells. We found common themes to the host response to cancer irrespective of mode of regression. Theme 1: Three regression phenotypes were identified: (1) nonregression, (2) regression, and (3) mixed regression. In nonregression, melanoma cells were epithelioid shaped and tightly packed. In regression, melanoma cells were spindle shaped and discohesive. Theme 2: In nonregression, B220+ B cells were small and located peritumor. In regression, B220+ B cells were intratumor and were plasmablasts/plasma cells. B cell numbers and distribution increased over time in spontaneous regression and was enhanced with immunotherapy. Theme 3: Ly6B.2+ neutrophils were in direct contact with dead/dying melanoma cells. The cytoplasm of the contacted melanoma cells displayed low/intermediate levels of Ly6B.2 protein, which suggested a role in melanoma cell death. Theme 4: At the peak of the adaptive immune response, in the regression tumors, most of the tumor mass were immune cells. Differentiators: The most striking difference between the two modes of regression was the presence of neutrophil extracellular traps (NETs)-like formations and geographic necrosis after immunotherapy treatment. Our preliminary data from patients with metastatic melanoma treated with anti-PD-1 therapy show that higher numbers of tumor-infiltrating B cells corresponded with longer progression-free survival. Beyond tumor regression, the increase in the B cell and neutrophil response could play a role in immunotherapy-induced adverse reactions.