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Targeting KDM4C upregulates the transcriptional activity of Cxcl10 to enhance the efficacy of combining radiotherapy and immunotherapy in lung cancer

ABSTRACT: The use of checkpoint blockade immunotherapy has revolutionized the field of cancer therapy. Although Immune checkpoint blockade (ICB) can achieve persistent response in several cancers, only 20-40% of patients can benefit from this therapeutic method. Preclinical and clinical evidence show that Radiotherapy (RT) can enhance tumor immunogenicity and improve the effects of immune checkpoint inhibitors. However, the actual outcomes are not satisfactory. Our previous studies revealed that the oncogene, Lysine-specific demethylase 4C (KDM4C) could regulate the radiosensitivity of lung cancer cells in vitro and in vivo. However, the role of KDM4C in antitumor immunity remains inconclusive. To that end, we analyzed the composition of infiltrating immune cells in our mouse tumor model using flow cytometry and found that KDM4C silencing could promote the intratumoral infiltration of CD8+ T cells. Further functional analysis showed that KDM4C silencing could promote proliferation, migration and activation of CD8+ T cells in vivo and in vitro and delay CD8+ T cells exhaustion. Mechanistically, using RNA-seq and Chip-PCR analysis, we determined that KDM4C silencing promotes the binding of H3K36me3 to the Cxcl10 promoter region to increase its transcriptional activity and thus induce CD8+ T cell-mediated antitumor response. Our results suggest that KDM4C-specific inhibitor, SD70 can reprogram the epigenetic state and improve the tumor microenvironment. More importantly, we found that the combined use of SD70, RT, and PD-L1 monoclonal antibodies exhibited the strongest antitumor effects and prolonged the survival time of tumor-bearing mice. Together, our findings suggest that a combination of KDM4C-targeted treatment, radiotherapy, and immune checkpoint blockade is safe and efficient for treating lung cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE178177 | GEO | 2022/02/18

REPOSITORIES: GEO

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Project description:Accumulating data support the concept that ionizing radiation therapy (RT) has the potential to convert the tumor into an in situ, individualized vaccine; however this potential is rarely realized by RT alone. Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that is activated by RT and inhibits the antigen-presenting function of dendritic cells and the differentiation of effector CD8+ T cells. Here we tested the hypothesis that TGFβ hinders the ability of RT to promote anti-tumor immunity. Development of tumor-specific immunity was examined in a pre-clinical model of metastatic breast cancer. Mice bearing established 4T1 mouse mammary carcinoma treated with pan-isoform specific TGFβ neutralizing antibody, 1D11, showed significantly improved control of the irradiated tumor and non-irradiated metastases, but no effect in the absence of RT. Notably, whole tumor transcriptional analysis demonstrated the selective upregulation of genes associated with immune-mediated rejection only in tumors of mice treated with RT+TGFβ blockade. Mice treated with RT+TGFβ blockade exhibited cross-priming of CD8+ T cells producing IFNγ in response to three tumor-specific antigens in tumor-draining lymph nodes, which was not evident for single modality treatment. Analysis of the immune infiltrate in mouse tumors showed a significant increase in CD4+ and CD8+ T cells only in mice treated with the combination of RT+TGFβ blockade. Depletion of CD4+ or CD8+ T cells abrogated the therapeutic benefit of RT+TGFβ blockade. These data identify TGFβ as a master inhibitor of the ability of RT to generate an in situ tumor vaccine, which supports testing inhibition of TGFβ during radiotherapy to promote therapeutically effective anti-tumor immunity. We used genome-wide microarray to depict main biological processes responsibles for the therapeutic benefit of the combination ofTGF-beta blockade and local radiotherapy. To gain a more comprehensice protrait of the effects of RT and TGFbeta blockade on gene expressionin tumors, we collected 4T1 tumors 4 days after completion of RT. Three tumors from each group were then subjected to RNA extraction and hybridization on affymetrix array.

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Targeting KDM4C upregulates the transcriptional activity of Cxcl10 to enhance the efficacy of combining radiotherapy and immunotherapy in lung cancer

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