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Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer.

ABSTRACT: Immune checkpoint blockade (ICB) has a limited effect on colorectal cancer, underlining the requirement of co-targeting the complementary mechanisms. Here, we identified prostaglandin E2 (PGE₂ ) receptor 4 (EP4) as the master regulator of immunosuppressive myeloid cells (IMCs), which are the major driver of resistance to ICB therapy. PGE₂ -bound EP4 promotes the differentiation of immunosuppressive M2 macrophages and myeloid-derived suppressor cells (MDSCs) and reduces the expansion of immunostimulated M1 macrophages. To explore the immunotherapeutic role of EP4 signaling, we developed a novel and selective EP4 antagonist TP-16. TP-16 effectively blocked the function of IMCs and enhanced cytotoxic T-cell-mediated tumor elimination in vivo. Cell co-culture experiments revealed that TP-16 promoted T-cell proliferation, which was impaired by tumor-derived CD11b⁺ myeloid cells. Notably, TP-16 and anti-PD-1 combination therapy significantly impeded tumor progression and prolonged mice survival. We further demonstrated that TP-16 increased responsiveness to anti-PD-1 therapy in an IMC-related spontaneous colorectal cancer mouse model. In summary, this study demonstrates that inhibition of EP4-expressing IMCs may offer a potential strategy for enhancing the efficacy of immunotherapy for colorectal cancer.

SUBMITTER: Lu W

PROVIDER: S-EPMC7799360 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer.

Lu Weiqiang W Yu Weiwei W He Jiacheng J Liu Wenjuan W Yang Junjie J Lin Xianhua X Zhang Yuanjin Y Wang Xin X Jiang Wenhao W Luo Jian J Zhang Qiansen Q Yang Huaiyu H Peng Shihong S Yi Zhengfang Z Ren Shancheng S Chen Jing J Siwko Stefan S Nussinov Ruth R Cheng Feixiong F Zhang Hankun H Liu Mingyao M

EMBO molecular medicine 20201207 1

Immune checkpoint blockade (ICB) has a limited effect on colorectal cancer, underlining the requirement of co-targeting the complementary mechanisms. Here, we identified prostaglandin E2 (PGE<sub>2</sub> ) receptor 4 (EP4) as the master regulator of immunosuppressive myeloid cells (IMCs), which are the major driver of resistance to ICB therapy. PGE<sub>2</sub> -bound EP4 promotes the differentiation of immunosuppressive M2 macrophages and myeloid-derived suppressor cells (MDSCs) and reduces the ...[more]

PMID: 33283987

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Project description:The roles of V-ATPase subunits in regulating CRC immune evasion remain unclear. By analyzing the Tumor and Immune System Interaction Database (TISIDB) for correlations between V-ATPases subunits and immune activities, we found that subunit ATP6V0A1 was inversely correlated with immune activities, especially with the proportions of effective or memory T cells in colon adenocarcinoma (COAD), suggesting an immunosuppressive role. With Atp6v0a1/ATP6V0A1 knockdown CRC cells and CRC syngeneic and xenograft mouse models, we confirmed that tumor cell-intrinsic ATP6V0A1 promotes the growth of CRC in an immune-dependent manner. To determine the type of immune cells contributing to ATP6V0A1-mediated immune evasion, we used single-cell transcriptome sequencing (sc-RNA seq) to analyze the ATP6V0A1-edited immune microenvironment in murine MC38 tumors. Holistic immune profiles in Atp6v0a1 knockdown and control MC38 tumors were compared. The results showed that Atp6v0a1 interference in MC38 cells increased the percentages of naïve T, effector T, and memory-like T-2 cells in the total T cell population while decreasing the percentages of exhausted T, Treg, and memory-like T-1 cells. Moreover, the percentages of granulocytes, monocytes, and dendritic cells within the myeloid population were increased in Atp6v0a1 knockdown-derived tumors, whereas the percentage of macrophages was decreased. Of all the immune cell subclusters, memory-like T-2 cells exhibited the most significantly increased cell count ratio in shv0a1 tumors vs. control tumors. In addition, memory-like T-2 cells expressed more effector markers than memory-like T-1 cells. These data suggest that MC38-derived ATP6V0A1 induced immunosuppressive tumor microenvironment (TME) and suppression of the effectiveness of memory-like T cells may play important roles in ATP6V0A1-regulated CRC immune evasion. The study provides directions to investigate the roles and mechanisms of ATP6V0A1 regulating anti-tumor immunity and thus shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.

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Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer.

Publications

Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer.

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