Targeting STAT3 Abrogates Tim-3 Upregulation of Adaptive Resistance to PD-1 Blockade on Regulatory T Cells of Melanoma

Abstract

BackgroundLess than 20% of melanoma patients respond to programmed cell death-1 (PD-1) blockade immunotherapies. Thus, it is crucial to understand the dynamic changes in the tumor microenvironment (TME) after PD-1 blockade, for developing immunotherapy efficacy.MethodsA 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 B16-F10 melanoma mice 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), and various immunosuppressive factors within tumor-infiltrated Treg cells after treatment with anti-PD-1 or the indicator transduction and activator of transcription 3 (STAT3) inhibitors. 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 PBMCs and the 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.

Manipulating the tumor immune microenvironment to improve cancer immunotherapy: IGF1R, a promising target

“…Activation of the JAK/STAT3 signaling, together with co-stimulatory pathways, has a profound immunosuppressive activity by inducing the tumor cell expression of genes including PD-L1 ( 33 , 34 ) and IDO1 ( 35 ), anti-inflammatory cytokines, such as IL-10 or TGF beta, and the angiogenic factor VEGF ( 27 ). STAT3 modulation acts directly or indirectly by decreasing dendritic cell (DC) activity ( 36 ), inhibiting the activation of cytotoxic CD8 + T cells ( 37 ) and NK cells ( 38 ), as well as stimulating the recruitment and differentiation of immunosuppressive macrophages ( 39 ), T-reg ( 40 – 42 ) and MDSC cells ( 43 ) in the TME.…”

Targeting tumor-infiltrating tregs for improved antitumor responses

“…Similarly, Xu et al. also found a significant increase in TIM3 expression within melanoma tumors of patients resistant to PD-1 treatment ( 155 , 156 ). Preclinical models have confirmed that combining PD-1 and TIM-3 targeting in anti-tumor therapy is more effective than using either approach individually ( 154 , 156 ).…”

The Multifaceted Role of STAT3 in NK-Cell Tumor Surveillance

“…The exact role of STAT3 in the regulation of these checkpoints has not been addressed in NK cells. In T regulatory cells, TIM-3 is strongly downregulated upon STAT3 inhibition suggesting a potential dependency of TIM-3 expression on STAT3 in other lymphocytes ( 162 ). It is attractive to speculate that LAG-3 expression in NK cells might be enhanced by STAT3 signaling.…”