Targeting HSPB1 Reduces Tumor Growth and Abrogates Treg-Mediated Tumor Immunosuppression
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ABSTRACT:
PROVIDER: PRJNA1306510 | ENA |
REPOSITORIES: ENA
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Project description:Colorectal cancer (CRC) shows limited responsiveness to immune-checkpoint blockade, highlighting the need for further investigation. The intratumoral Treg/CD8⁺ T-cell ratio serves as a predictive biomarker for therapeutic efficacy. Here, we first demonstrate that targeting HSPB1 lowers this ratio and confers therapeutic benefit in CRC. Methods. Candidate genes were identified by integrative single-cell transcriptomics and spatial transcriptomics, followed by survival analyses of TCGA cohorts. Functional interrogation was performed using CRISPR-Cas9 engineered knockout cell lines. Subcutaneous tumor models were established, and the immune microenvironment was characterized by multiparametric flow cytometry. Mechanistic validation was achieved through bulk RNA-seq and complementary functional assays. Results. Single-cell profiling identified HSPB1 as a determinant of the intratumoral Treg/CD8⁺ T-cell ratio, and TCGA analysis showed its prognostic relevance in CRC. Spatial transcriptomics revealed colocalization of HSPB1-expressing tumor cells with Tregs. Subcutaneous tumor models demonstrated that CRISPR-mediated HSPB1 deletion or pharmacologic inhibition markedly suppressed tumor growth and reprogrammed the Treg-dominated microenvironment. In vitro polarization assays confirmed that targeting HSPB1 selectively restrains Treg differentiation without affecting Th17. Integrated transcriptomic and functional studies further elucidated that HSPB1 orchestrates CCL20–CCR6 mediated Treg recruitment, thereby shaping the immunosuppressive milieu within colorectal tumors.Conclusions. Targeting HSPB1 exerts dual anti-tumor effects by directly suppressing neoplastic proliferation and concurrently alleviating Treg-mediated immunosuppression within the tumor microenvironment.
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Project description:Ovarian cancer has the worst prognosis in major gynecological cancers. Current therapies includes platinum, taxol, angiogenesis inhibitor, PARP inhibitor. However, most ovarian cancer patients develop resistance. Identification of more pro-tumor factors in ovarian cancer may shed insight into ovarian cancer biology and therapy. In this study, we find ZKSCAN3, a zinc-finger transcription factor is overexpressed in ovarian cancer. We show ZKSCAN3 promotes ovarian cancer cell proliferation. Through RNA-sequencing and ChIP-sequencing, HSPB1 is identified as a target gene of ZKSCAN3. HSPB1 expression is significantly decreased by suppressing ZKSCAN3. Suppressing HSPB1 expression inhibits ovarian cancer cell proliferation as well. In contrast, expressing exogenous HSPB1 partially rescues the cell proliferation in ZKSCAN3 knock-down cells. Collectively, our study uncovers a functional ZKSCAN3-HSPB1 axis that promotes ovarian cancer cell proliferation.
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Project description:Through a diversity of functional lineages, cells of the innate and adaptive immune system either drive or constrain immune reactions within tumors. Thus, while the immune system has a powerful ability to recognize and kill cancer cells, this function is often suppressed preventing clearance of disease. The transcription factor (TF) BACH2 controls the differentiation and function of multiple innate and adaptive immune lineages, but its role in regulating tumor immunity is not known. Here, we demonstrate that BACH2 is required to establish immunosuppression within tumors. We found that growth of subcutaneously implanted tumors was markedly impaired in Bach2-deficient mice and coincided with intratumoral activation of both innate and adaptive immunity but was dependent upon adaptive immunity. Analysis of tumor-infiltrating lymphocytes in Bach2-deficient mice revealed high frequencies of CD4+ and CD8+ effector cells expressing the inflammatory cytokine IFN-γ. Lymphocyte activation coincided with reduction in the frequency of intratumoral CD4+ Foxp3+ regulatory T (Treg) cells. Mechanistically, Treg-dependent inhibition of CD8+ T cells was required for BACH2-mediated tumor immunosuppression. These findings demonstrate that BACH2 is a key component of the molecular programme of tumor immunosuppression and identify a new target for development of therapies aimed at reversing immunosuppression in cancer. Analysis of tumor-infiltrating lymphocytes in Bach2-deficient mice revealed high frequencies of CD4+ and CD8+ effector cells expressing the inflammatory cytokine IFN-γ. Lymphocyte activation coincided with reduction in the frequency of intratumoral CD4+ Foxp3+ regulatory T (Treg) cells. Mechanistically, Treg-dependent inhibition of CD8+ T cells was required for BACH2-mediated tumor immunosuppression.
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