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Overcoming cancer-associated fibroblast-induced immunosuppression by anti-interleukin-6 receptor antibody.

ABSTRACT: Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which IL-6 induces tumor immunosuppression. In clinical samples, IL-6 expression was significantly correlated with α-smooth muscle actin expression, and high IL-6 cases showed tumor immunosuppression. Multivariate analysis showed that IL-6 expression was an independent prognostic factor. In vitro, IL-6 contributed to cell proliferation and differentiation into CAFs. Moreover, IL-6 increased hypoxia-inducible factor 1α (HIF1α) expression and induced tumor immunosuppression by enhancing glucose uptake by cancer cells and competing for glucose with immune cells. MR16-1, a rodent analog of anti-IL-6 receptor antibody, overcame CAF-induced immunosuppression and suppressed tumor progression in immunocompetent murine cancer models by regulating HIF1α activation in vivo. The anti-IL-6 receptor antibody could be systemically employed to overcome tumor immunosuppression and improve patient survival with various cancers. Furthermore, the tumor immunosuppression was suggested to be induced by IL-6 via HIF1α activation.

SUBMITTER: Nishiwaki N

PROVIDER: S-EPMC9916502 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Overcoming cancer-associated fibroblast-induced immunosuppression by anti-interleukin-6 receptor antibody.

Nishiwaki Noriyuki N Noma Kazuhiro K Ohara Toshiaki T Kunitomo Tomoyoshi T Kawasaki Kento K Akai Masaaki M Kobayashi Teruki T Narusaka Toru T Kashima Hajime H Sato Hiroaki H Komoto Satoshi S Kato Takuya T Maeda Naoaki N Kikuchi Satoru S Tanabe Shunsuke S Tazawa Hiroshi H Shirakawa Yasuhiro Y Fujiwara Toshiyoshi T

Cancer immunology, immunotherapy : CII 20230210 7

Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which ...[more]

PMID: 36764954

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Project description:Background: Previous studies revealed that colonic cancer-associated fibroblasts (CAFs) are associated with the modulation of the colon tumor microenvironment (TME). However, identification of key transcriptomes and their correlations with the survival prognosis, immunosuppression, tumor progression, and metastasis in colon cancer remains lacking. Methods: We used the GSE46824, GSE70468, GSE17536, GSE35602, and the cancer genome atlas (TCGA) colon adenocarcinoma (COAD) datasets for this study. We identified the differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, hub genes, and survival-associated genes in colon cancer. Finally, we investigated the correlation of key genes with the survival prognosis, immunosuppression, and metastasis. Results: We identified 246 common DEGs between the GSE46824 and GSE70468 datasets of colonic CAFs, which included 72 upregulated and 174 downregulated genes. The upregulated pathways are mainly involved with cancers and cellular signaling, and downregulated pathways are involved with immune regulation and cellular metabolism. The search tool for the retrieval of interacting genes (STRING)-based analysis identified 15 hub genes and 9 significant clusters in colonic CAFs. The upregulation of CTHRC1, PDGFC, PDLIM3, NTM, and SLC16A3 and downregulation of FBN2 are correlated with a shorter survival time in colon cancer. The CTHRC1, PDGFC, PDLIM3, and NTM genes are positively correlated with the infiltration of tumor-associated macrophages (TAM), macrophages, M2 macrophages, the regulatory T cells (Tregs), T cell exhaustion, and myeloid-derived suppressor cells (MDSCs), indicating the immunosuppressive roles of these transcriptomes in colon cancer. Moreover, the CTHRC1, PDGFC, PDLIM3, NTM, and SLC16A3 genes are gradually increased from normal tissue to the tumor and tumor to the metastatic tumor, and FBN2 showed the reverse pattern. Furthermore, the CTHRC1, FBN2, PDGFC, PDLIM3, and NTM genes are positively correlated with the metastatic scores in colon cancer. Then, we revealed that the expression value of CTHRC1, FBN2, PDGFC, PDLIM3, NTM, and SLC16A3 showed the diagnostic efficacy in colonic CAFs. Finally, the expression level of CTHRC1, PDGFC, and NTM genes are consistently altered in colon tumor stroma as well as in the higher CAFs-group of TCGA COAD patients. Conclusion: The identified colonic CAFs-derived key genes are positively correlated with survival prognosis, immunosuppression, tumor progression, and metastasis.

Dataset Information

Overcoming cancer-associated fibroblast-induced immunosuppression by anti-interleukin-6 receptor antibody.

Publications

Overcoming cancer-associated fibroblast-induced immunosuppression by anti-interleukin-6 receptor antibody.

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