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Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
CCL5 hiCD4+ T Cells Regulate Macrophage Polarization and Promote Immunotherapy Response in Bladder Cancer
Weiming Luo1, Yapeng Wang1, Haitao Wang1
1Department of Urology, Daping Hospital, Army Medical University, Chongqing, People's Republic of China.
Abstract:
Immune checkpoint inhibitors (ICI) have transformed cancer therapy, yet their efficacy remains limited to a subset of patients, underscoring the need for robust predictive biomarkers and deeper mechanistic insights into treatment resistance. In this study, we identified a population of CCL5hiCD4+ T cells that were characterized by memory-like activation markers and strongly correlated with ICI therapeutic responses in bladder cancer. Functionally, these T cells enhanced antitumor immunity by promoting M1-like macrophage polarization through CCL5/CCR1 signaling. Importantly, tumor-derived prostaglandin E2 (PGE2) acted as a critical microenvironmental factor that suppressed the differentiation of CCR6hiCD4+ T cells into immunostimulatory CCL5hiCD4+ T cells, thereby driving resistance to ICI therapy. These findings extend the understanding of CD4+ T-cell heterogeneity and its role in shaping immune responses to ICI. By elucidating that CCL5hiCD4+ T cells enhance myeloid-mediated tumor control and that tumor-derived PGE2 disrupts CCL5hiCD4+ T-cell differentiation to promote immune evasion, this work highlights potential therapeutic strategies to improve ICI efficacy in bladder cancer.
Significance:
CCL5 hiCD4+ T cells with memory-like activated characteristics enhance antitumor immunity in bladder cancer by reprogramming macrophages, supporting the potential of these cells as biomarkers and targets to enhance immunotherapy efficacy.
Insights
Researchers discovered specific CD4+ T cells (CCL5hi) that predict successful immune checkpoint inhibitor (ICI) therapy in bladder cancer. Tumor-produced prostaglandin E2 (PGE2) hinders these cells, causing resistance to ICI treatment.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but benefit only a subset of patients.
- Identifying biomarkers and understanding resistance mechanisms are crucial for improving ICI efficacy.
Purpose of the Study:
- To identify CD4+ T cell populations associated with ICI response in bladder cancer.
- To elucidate the mechanisms underlying ICI resistance.
- To explore therapeutic strategies for enhancing ICI efficacy.
Main Methods:
- Flow cytometry and single-cell analysis to characterize T cell populations.
- In vitro co-culture assays to assess T cell function and macrophage polarization.
- Analysis of tumor microenvironment factors, including prostaglandin E2 (PGE2).
Main Results:
- A distinct population of CCL5hi-CD4+ T cells, expressing memory-like activation markers, strongly correlated with positive ICI responses in bladder cancer.
- These CCL5hi-CD4+ T cells promote anti-tumor immunity by driving M1-like macrophage polarization via CCL5/CCR1 signaling.
- Tumor-derived PGE2 was identified as a key factor suppressing the differentiation of immunostimulatory CCL5hi-CD4+ T cells, leading to ICI resistance.
Conclusions:
- CCL5hi-CD4+ T cells are key drivers of myeloid-mediated anti-tumor immunity and potential biomarkers for ICI response.
- Tumor-derived PGE2 disrupts CCL5hi-CD4+ T cell differentiation, contributing to immune evasion and ICI resistance.
- Targeting PGE2 or enhancing CCL5hi-CD4+ T cell function may represent novel therapeutic strategies to improve ICI efficacy in bladder cancer.
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