Abstract PO064: Baseline steroids impair immunotherapy efficacy in a mouse model of melanoma
Authors: Ferreira Michelle , Daniels Drew , Bosenberg Marcus 
Published: February 2021

Abstract
While checkpoint inhibition has changed the landscape of treatment for multiple tumor types, many questions remain, particularly about the use of concurrent immunosuppressive agents such as steroids. Many patients starting immunotherapy are on baseline steroids, such as patients with autoimmune conditions or patients with brain metastases. In vitro, steroids are well-known to disrupt dendritic cell priming, activation, and maturation, steps that are key for appropriate mobilization of CD8+ cytotoxic T cells that are critical for antitumor immunity, but few studies directly study the interaction of baseline steroids with immunotherapy. In this work, we studied this interaction using the YUMMER model (Yale University Mouse Melanoma Exposed to Radiation) 1.7 model, a syngeneic cell line that originates from BrafV600E; Pten-/-; and Cdkn2a-/- genetically engineered mouse melanomas. YUMMER1.7 (YR1.7) has been irradiated to increase immune system recognition via induction of neoantigens and thus exhibits reproducible responses to anti-CTLA4 and anti-PD1 immunotherapy. In this study, 6-8 week old C57Bl6/j mice were injected subcutaneously with 500K YR1.7 cells and treated with dual biweekly injections of anti-CTLA4 and anti-PD1 therapy starting on day 7 (dCPI, n = 10), dCPI + baseline steroids administered on the day prior to tumor implantation and every other day for 10 days thereafter (n = 10), baseline steroids alone (n = 10), or nothing (n = 10). We found that survival of mice receiving baseline steroids with dCPI was significantly reduced (p = 0.0355) compared to mice receiving only dCPI. Tumor volumes on day 18 were significantly larger (p = 0.0052) in the group both dCPI and baseline steroids compared to the group receiving only dCPI. In mice receiving dCPI with steroids started on day 7, as opposed to day -1, this reduction in effect was not seen. Serum cytokine analysis showed that on day 12, mice receiving baseline steroids had significantly lower concentrations of many crucial antitumor cytokines, most notably IFN-gamma, MIG, IP-10, RANTES, TARC, IL-12, IL-7, IL-15, MIP-1a, and 6CKine. Weights of tumor-draining lymph nodes were significantly lower from mice receiving baseline steroids and dCPI (p = 0.0411), suggesting that steroids blunted the proliferation of antitumor immune cells in the LN. Finally, IHC staining demonstrated that CD8 cells were absent in the tumor microenvironment of mice receiving baseline steroids. Together, these data suggest that baseline steroids may be deleterious to immunotherapy-induced antitumor immunity, likely through impairing T-cell activation and migration, possibly through interfering with DC priming. Clinically, this raises the question of whether patients on baseline steroids on the cusp of initiating immunotherapy should be switched to a more narrow immunosuppressive regimen that achieves disease control without compromising the potentially helpful effect of immunotherapy.
Citation Format: Michelle Ferreira, Drew Daniels, Marcus Bosenberg. Baseline steroids impair immunotherapy efficacy in a mouse model of melanoma [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO064.