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Inhibition of STAT3 Promotes Effector T Cell Infiltration But also Immunosuppression in the HCC Tumor
Taketo Sasaki1, Kohei Shigeta2, Shuji Kitahara3
1Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
Background/Aim:
STAT3 is involved in the progression of several cancers, and has been proposed as target for therapy. Indeed, the multitargeted tyrosine kinase inhibitor drug regorafenib, which indirectly inhibits STAT3, can significantly enhance the effects of anti-programmed death receptor (PD)-1 therapy in hepatocellular carcinoma (HCC) models. Here, we studied the impact of a direct STAT3 inhibitor on the tumor microenvironment and PD-1 blockade efficacy in HCC models.
Materials And Methods:
Orthotopic mouse models of HCC (RIL-175 and HCA-1 grafts in syngeneic mice) were used to test the efficacy of the selective STAT3 inhibitor STX-0119 alone or combined with anti-PD-1 antibodies. We evaluated the effects of therapy on tumor vasculature and the immune microenvironment using immunofluorescence (IF), cell viability assay and quantitative real-time (qRT)-PCR in tumor tissues.
Results:
Combining anti-PD-1 antibodies with a STX-0119 failed to show a growth delay or survival benefit compared to each agent alone or control in any of the HCC models. Interestingly, evaluation of intratumoral CD8+ T cell infiltration by IF showed a significant increase after one-week treatment with STX-0119 (p=0.034). However, STX-0119 treatment simultaneously promoted increased immunosuppression in the tumor microenvironment by increasing the proportion of Tregs, tissue hypoxia and α-SMA activated cancer-associated fibroblasts (CAFs) measured by IF. Consistent with these findings, we found increased immature tumor vessels by IF and VEGF, Tgf-β and Vash2 expression by qPCR.
Conclusion:
Pharmacologic STAT3 inhibition could significantly enhance CD8+ T cell infiltration in HCC but also significantly alter the immunosuppression and vascular abnormalization in the tumor microenvironment.
Insights
A direct STAT3 inhibitor increased T cell infiltration in liver cancer models but also promoted immunosuppression and abnormal blood vessels, failing to improve anti-PD-1 therapy efficacy. This highlights complex effects on the tumor microenvironment.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Signal transducer and activator of transcription 3 (STAT3) is implicated in cancer progression and is a potential therapeutic target.
- Regorafenib, a multitargeted tyrosine kinase inhibitor, indirectly inhibits STAT3 and enhances anti-programmed death receptor (PD)-1 therapy in hepatocellular carcinoma (HCC) models.
- Investigating direct STAT3 inhibition offers insights into modulating the tumor microenvironment and improving immunotherapy response.
Purpose of the Study:
- To evaluate the impact of a direct STAT3 inhibitor, STX-0119, on the tumor microenvironment.
- To assess the efficacy of combining STX-0119 with anti-PD-1 antibodies in HCC models.
- To understand how STAT3 inhibition affects immune cell infiltration, immunosuppression, and tumor vasculature.
Main Methods:
- Orthotopic mouse models of HCC (RIL-175 and HCA-1 grafts) were utilized.
- Mice were treated with STX-0119 alone, anti-PD-1 antibodies alone, or the combination.
- Tumor tissues were analyzed using immunofluorescence (IF), cell viability assays, and quantitative real-time PCR (qRT-PCR) to assess vasculature, immune cells, and gene expression.
Main Results:
- The combination of STX-0119 and anti-PD-1 antibodies did not improve tumor growth delay or survival compared to monotherapy or control.
- STX-0119 significantly increased intratumoral CD8+ T cell infiltration.
- STX-0119 also increased immunosuppression markers, including regulatory T cells (Tregs), tissue hypoxia, alpha-smooth muscle actin (α-SMA)-activated cancer-associated fibroblasts (CAFs), and immature tumor vessels, alongside increased VEGF, Tgf-β, and Vash2 expression.
Conclusions:
- Pharmacologic STAT3 inhibition can enhance CD8+ T cell infiltration in HCC.
- However, STAT3 inhibition also promotes immunosuppression and vascular abnormalities within the tumor microenvironment.
- These complex effects may limit the efficacy of combining direct STAT3 inhibitors with anti-PD-1 therapy in HCC.
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