Abstract A179: Targeting UCP2 pathway in melanoma cells reprograms the tumor microenvironment and initiates antitumor immune cycle

Immune checkpoint blockade treatment displays promising therapeutic efficiency in different cancer types. However, a significant proportion of patients are refractory to this treatment due to lack of T-cell infiltration in tumors, a phenotype known as “cold tumors.” To improve the therapeutic benefits of checkpoint blockade, it is crucial to address how to escalate T-cell infiltration into tumors. Here, we characterized melanoma patients in The Cancer Genome Atlas (TCGA) into either high or low T-cell antitumor responses. We then identified the mRNA expression level of mitochondrial uncoupling protein 2 (UCP2) positively correlates with T-cell antitumor immune responses and prolonged patients survival. By using murine melanoma model, we revealed that overexpressing UCP2 in melanoma cells elevates CD8+ T-cell infiltration into the tumor microenvironment (TME) in a conventional type 1 dendritic cell (cDC1)-dependent manner and normalize tumor neovasculature. Mechanistically, UCP2 induction in tumor cells alters the cytokine milieu in tumors and stimulates the recruitment of cDC1 through a IRF5-CXCL10 chemokine axis. Hence, enhancing the expression of UCP2 in melanoma cells provides immunostimulatory shift by engaging the cDC1-CD8+ T-cell dependent antitumor immune cycle in the TME. Interestingly, we demonstrated that inducing UCP2 expression in melanoma cells by genetic approach or administration of rosiglitazone, an approved antidiabetic PPAR agonist, can sensitize PD-1 blockade-resistant melanomas to anti-PD-1 antibody treatment. Accordingly, our data indicate that targeting UCP2 in melanoma cells can be a potent strategy to increase antitumor response to checkpoint blockades in non-T-cell-inflamed tumors. Citation Format: Wan-Chen Cheng. Targeting UCP2 pathway in melanoma cells reprograms the tumor microenvironment and initiates antitumor immune cycle [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A179.