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PBRM1 Deficiency Reshapes an Immune Suppressive Microenvironment Through Epigenetic Tuning of PBRM1-KDM5C-IL6 Axis in
Wenjiao Xia1, Hongru Wang1,2, Yu Dong1
1Department of Urology, Center for Oncology Medicine, and International School of Medicine, International Institutes of Medicine, The Fourth Affiliated Hospital of School of Medicine, Zhejiang University, Yiwu, China.
Abstract:
Polybromo 1 (PBRM1) ranks as the second most commonly mutated gene in clear cell renal cell carcinoma (ccRCC), while its role in immune escape remains elusive. We developed a PBRM1-knockout mice model to perform single-cell RNA sequencing, which demonstrated a substantial population of immunosuppressive tumor-associated macrophages (TAMs) in the spontaneous tumor, with consistent results from an orthotopic renal tumor mice model. Multiplex immunohistochemistry of clinical samples revealed that PBRM1-deficient tumors exhibited increased M2 TAMs in both stroma and parenchyma, while CD8+ T cells were restricted to the stroma. M2 TAMs and cancer-associated fibroblasts (CAFs) interacted to construct a tumor immune barrier, preventing CD8+ T cell infiltration. Mechanistically, PBRM1 modulated interleukin-6 (IL-6) expression by recruiting lysine demethylase 5C (KDM5C), thereby orchestrating M2 polarization of TAMs. Blocking IL-6 synergistically augmented the antitumor efficacy of anti-PD-1 therapy. Our findings revealed a PBRM1-KDM5C-IL-6 axis that influenced antitumor immunity, indicating a potential immunotherapeutic strategy in PBRM1-deficient ccRCC.
Insights
Loss of Polybromo 1 (PBRM1) in clear cell renal cell carcinoma promotes immune suppression by increasing M2 tumor-associated macrophages (TAMs). Targeting the PBRM1-KDM5C-IL-6 pathway may enhance immunotherapy efficacy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Polybromo 1 (PBRM1) is frequently mutated in clear cell renal cell carcinoma (ccRCC).
- The function of PBRM1 in tumor immune evasion is not well understood.
Purpose of the Study:
- To investigate the role of PBRM1 in ccRCC immune microenvironment.
- To elucidate the mechanism by which PBRM1 deficiency impacts tumor immunity.
- To explore potential immunotherapeutic strategies for PBRM1-deficient ccRCC.
Main Methods:
- Developed PBRM1-knockout mice models for spontaneous and orthotopic renal tumors.
- Performed single-cell RNA sequencing and multiplex immunohistochemistry.
- Investigated the interaction between PBRM1, KDM5C, and IL-6 signaling.
Main Results:
- PBRM1 deficiency led to increased immunosuppressive M2 tumor-associated macrophages (TAMs) and restricted CD8+ T cell infiltration.
- M2 TAMs and cancer-associated fibroblasts formed a barrier hindering T cell entry.
- PBRM1 deficiency promoted M2 TAM polarization via the KDM5C-IL-6 axis.
- Blocking IL-6 enhanced anti-PD-1 therapy efficacy.
Conclusions:
- The PBRM1-KDM5C-IL-6 axis is crucial for regulating antitumor immunity in ccRCC.
- Targeting this axis offers a promising immunotherapeutic approach for PBRM1-deficient ccRCC.
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