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.
Highlights
Less than 20% of melanoma patients respond to programmed cell death-1 (PD-1) blockade immunotherapies
We analyzed the co-expression of T cell immunoglobulin and mucindomain containing-3 (Tim-3) and PD-1 with Signal transduction and activator of transcription 3 (STAT3) in the melanoma patients and the Regulatory T (Treg) cells
We found a significant upregulation of Tim-3 on Treg cells after anti-PD-1 therapy in vitro (Figure 2H, p < 0.05), which was similar to Peripheral blood mononuclear cells (PBMCs)
Summary
Less than 20% of melanoma patients respond to programmed cell death-1 (PD-1) blockade immunotherapies. It is crucial to understand the dynamic changes in the tumor microenvironment (TME) after PD-1 blockade, for developing immunotherapy efficacy. It is essential to comprehend the vibrant alterations of adaptive resistance within the tumor microenvironment (TME) after PD-1 blockade and explore novel intervention targets as a possible therapy for improving the efficacy of immunotherapy. One prominent strategy includes blocking dual immune harrier receptors in T cells by targeting both the inhibitory T cell immunoglobulin and mucindomain containing-3 (Tim-3) and PD-1 [7]. The dynamic changes of Tim-3 on Treg cells in anti-PD-1 nonresponse melanoma patients, the potential cross-talk of PD-1 and Tim-3 in tumor-infiltrating lymphocytes (TILs), and the mechanism of the regulation of the two checkpoint receptors above have not been elucidated
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