Abstract 70: Obesity-induced impairment of antitumor immunity is associated with an immunosuppressive tumor immune landscape

Obesity is associated with an increased risk and progression in a variety of cancers. In melanoma, obesity is associated with an increased risk of recurrence following surgical resection which may reflect immune escape of cancer surveillance. We sought to examine the impact of obesity on antitumor immunity in an immunogenic preclinical melanoma model.Male C57/Bl6 mice were fed a 45% fat diet or 10% fat diet for 12 months resulting in obese (body weight 52.8g ±1.3) vs control mice (body weight 38.8g ±2.2). For these studies, we utilized the YUMMER cell line, a C57BL/6J syngeneic melanoma cell line with three driver mutation/deletions (BrafV600E, Pten-/-, Cdkn2a-/-), irradiated to mimic the high mutation burden of human melanoma. 0.5x106 YUMMER cells were subcutaneously injected into the flank of aged (13 month old) control and obese mice. After 14 days post injection, tumors in control mice either had growth arrest or regression. In contrast, all obese mice exhibited progressively growing tumors with 6-fold greater tumor weights after 21 days as compared to control (1.3g ±0.4 vs 0.23g ±0.06). CyTOF analysis of tumor-infiltrating immune cells at day 21 showed 2-fold decrease in the percentage of CD4 T cells in tumors from obese mice (9.8% vs 21.1% of CD45). In addition, obesity resulted in 4-fold increase in the frequency of intratumoral Treg (26.1% vs 8.3% of CD3CD4 cells) and CD8/Treg ratio was 2-fold reduced in obese mice. In contrast to prior findings in obese mice bearing B16 melanomas, the percentage of CD8 T cells expressing PD1 was similar (80.4% vs 74.3%), but we found 2-fold higher frequency of CD8PD1 T cells co-expressing TIM3 and LAG3 in tumors from obese mice (43.3% vs 23.0%). Moreover, obesity also attenuated the frequency of tumor-infiltrating cDC2 (1.4% vs 3.5% of CD45) but did not affect NK cells or B cell proportions. Furthermore, the ratio of tumor infiltrating myeloid cells to T cells was higher in obese mice (1.94:1 vs 0.82:1). Moreover, myeloid cells from obese mouse tumors had higher expression of PDL1, CD206, and CD38 markers.Our findings provide evidence that obesity impairs antitumor immunity by modulating the relative abundance of intratumoral immune cell populations and their phenotypes to promote immunosuppressive microenvironment. These findings will be validated in subsequent studies and examined in human specimens. Citation Format: Barbara Pazdrak, Duncan Mak, William Damsky, Marcus Bosenberg, Brooklyn Lochmann, Matthew Gubin, Jennifer McQuade. Obesity-induced impairment of antitumor immunity is associated with an immunosuppressive tumor immune landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 70.