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Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer.

ABSTRACT: Impressive clinical benefit is seen in clinic with PD-1 inhibitors on portion of cancer patients. Yet, there remains an urgent need to develop effective synergizers to expand their clinical application. Tumor-associated macrophage (TAM), a type of M2-polarized macrophage, eliminates or suppresses T-cell-mediated anti-tumor responses. Transforming TAMs into M1 macrophages is an attractive strategy of anti-tumor therapy. Here, we conducted a high-throughput screening and found that Carfilzomib potently drove M2 macrophages to express M1 cytokines, phagocytose tumor cells, and present antigens to T cells. Mechanistically, Carfilzomib elicited unfolded protein response (UPR), activated IRE1α to recruit TRAF2, and activated NF-κB to transcribe genes encoding M1 markers in M2 macrophages. In vivo, Carfilzomib effectively rewired tumor microenvironment through reprogramming TAMs into M1-like macrophages and shrank autochthonous lung cancers in transgenic mouse model. More importantly, Carfilzomib synergized with PD-1 antibody to almost completely regress autochthonous lung cancers. Given the safety profiles of Carfilzomib in clinic, our work suggested a potentially immediate application of combinational treatment with Carfilzomib and PD-1 inhibitors for patients with solid tumors.

SUBMITTER: Zhou Q

PROVIDER: S-EPMC8749493 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer.

Zhou Qian Q Liang Jinxia J Yang Tong T Liu Jin J Li Bo B Li Yingchang Y Fan Zhenzhen Z Wang Weida W Chen Wensheng W Yuan Sujing S Xu Meng M Xu Qigui Q Luan Zhidong Z Xia Zhongjun Z Zhou Penghui P Huang Yadong Y Chen Liang L

EMBO molecular medicine 20211213 1

Impressive clinical benefit is seen in clinic with PD-1 inhibitors on portion of cancer patients. Yet, there remains an urgent need to develop effective synergizers to expand their clinical application. Tumor-associated macrophage (TAM), a type of M2-polarized macrophage, eliminates or suppresses T-cell-mediated anti-tumor responses. Transforming TAMs into M1 macrophages is an attractive strategy of anti-tumor therapy. Here, we conducted a high-throughput screening and found that Carfilzomib pot ...[more]

PMID: 34898004

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Project description:Background: Tumor progression and limited benefits of immune checkpoint blockade (ICB) therapy have been two major challenges in the clinical management of colorectal cancer (CRC). The objective of our research was to explore the role of PLCG2 in CRC progression, tumor microenvironment, and potentiating ICB therapy. Methods: Based on bioinformatics analysis and a prospective clinical observational study, the expression, prognostic significance, and clinical relevance of PLCG2 in CRC were unveiled. The single-cell and spatial transcriptome revealed the role of PLCG2 in shaping the heterogeneity of the CRC tumor microenvironment. The biological function of PLCG2 was validated by in vivo and in vitro experiments. The underlying mechanisms were elucidated by RNA-seq, western blotting, qRT-PCR, and multicolor immunofluorescence. The multiplex immunohistochemistry and flow cytometry were adopted to clarify the immunomodulatory role of PLCG2 in facilitating CRC immune escape. The translational value of targeting PLCG2 to potentiate the efficacy of ICB therapy and synergistic therapy to improve prognosis was explored in the preclinical animal models. Results: In CRC, PLCG2 exhibited high expression levels and was strongly associated with poor prognosis and advanced clinicopathological characteristics of patients. The single-cell transcriptome shed light on its important role in cell communication and the development and differentiation of immune cells. The spatial transcriptome described the spatial distribution of PLCG2 in CRC tissues. Further mechanistic analysis demonstrated that PLCG2 could promote proliferation, invasion, metastasis, epithelial-mesenchymal transition, and cell cycle regulation and inhibit apoptosis of CRC cells via the Akt-mTOR pathway activation. Furthermore, PLCG2 was found to contribute greatly to the immunosuppressive microenvironment and enhanced immune escape as it significantly suppressed the infiltration and functional activation of CD8+ T cells and promoted the infiltration of Treg cells as well as PD-1 and PD-L1 expression. Meanwhile, knockdown of PLCG2 could potentiate the efficacy of ICB therapy. Conclusion: In summary, we have identified for the first time that PLCG2 could be considered a precise biomarker and promising therapeutic target for predicting CRC prognosis, optimizing individualized treatment, reversing CRC immune escape, and overcoming resistance to ICB therapy.

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Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer.

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Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer.

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