Targeting STAT3 abrogates Tim-3 upregulation of adaptive resistance to PD-1 blockade on regulatory T cells of melanoma

Background: Programmed cell death-1 (PD-1) blockade immunotherapies have demonstrated excellent clinical benefits in multiple cancers, but < 20% of melanoma patients respond to these treatments. Thus, it is crucial to understand for getting awareness of the dynamic changes vibrant transformations in the tumor microenvironment (TME) after PD-1 blockade, in exploring novel intervention targets as a potential therapy, for developing immunotherapy efficacy. MethodsTo ascertain the differentially expressed between PDCD1 low and PDCD1 high subsets and further PDCD1 related genes in skin cutaneous melanoma (SKCM) patients, a genomic analysis was conducted by The Cancer Genome Atlas (TCGA) datasets and web platform TIMER2.0 datasets. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Peripheral blood mononuclear cells (PBMCs), regulatory T (Treg) cells and B16F10 melanoma mouse were used as models. The cellular and molecular characteristics and mechanisms of Treg cells in melanoma were assessed by performing gene expression studies, immunohistochemistry, RNA sequencing, and flow cytometry.ResultsHere, we evaluate the countenance of T cell immunoglobulin and mucin-domain containing-3 (Tim-3), various immunosuppressive factors within tumor infiltrated regulatory T (Treg) cells after treated with anti-PD-1 or the indicator transduction and activator of transcription 3 (STAT3) inhibitors. Tim-3 gene is expressed differentially between PD-1 low and PD-1 high subsets from TCGA datasets and melanoma patients’ biopsies. Increased expression of Tim-3 is markedly observed within the tissues of the PD-1 blockade resistance of melanoma patients. Targeting STAT3 significantly boosts the response of resistant-PD-1 therapy within the melanoma mouse model. Mechanistically, the manifestation of STAT3 decreases the expression of Tim-3 and various cytokines in the purified Treg cells from individual peripheral blood mononuclear cells (PBMCs) and murine melanoma model, limiting the immunosuppression of Treg cells. ConclusionsOur findings indicate that Tim-3 expression on Treg cells within the TME is STAT3-dependent, providing support to STAT3 as a target and enhancing the immunotherapy for patients suffering from melanoma.