ANGPTL2‐mediated epigenetic repression of MHC‐I in tumor cells accelerates tumor immune evasion

Loss or downregulation of major histocompatibility complex class I (MHC‐I) contributes to tumor immune evasion. We previously demonstrated that angiopoietin‐like protein 2 (ANGPTL2) promotes tumor progression using a Xp11.2 translocation renal cell carcinoma (tRCC) mouse model. However, molecular me...

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Bibliographic Details
Published in:	Molecular oncology Vol. 17; no. 12; pp. 2637 - 2658
Main Authors:	Kadomatsu, Tsuyoshi, Hara, Chiaki, Kurahashi, Ryoma, Horiguchi, Haruki, Morinaga, Jun, Miyata, Keishi, Kurano, Sohtaro, Kanemaru, Hisashi, Fukushima, Satoshi, Araki, Kimi, Baba, Masaya, Linehan, W. Marston, Kamba, Tomomi, Oike, Yuichi
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-12-2023 Wiley
Subjects:	Angiopoietin Angiopoietin-Like Protein 2 Angiopoietin-like Proteins - genetics Angiopoietin-like Proteins - metabolism ANGPTL2 Animals Antigen presentation Cancer Carcinoma, Renal Cell - genetics CD8 antigen Cell-mediated immunity Cloning Cytotoxicity Disease Models, Animal Epigenetic inheritance Epigenetic Repression Epigenetics Epithelial cells Ethylenediaminetetraacetic acid Flow cytometry Genes Genomes H3K27me3 Histocompatibility Antigens Class I - genetics Immune evasion Immune response (cell-mediated) Integrins Invoices Kidney cancer Kidney Neoplasms Kinases Leukocytes Lymphocytes Lymphocytes T Major histocompatibility complex Metastases MHC‐I Mice Molecular modelling Mutation Plasmids Polycomb group proteins PRC2 Proteins Reagents Renal cell carcinoma Scientific equipment and supplies industry T cell receptors T cells Tumor antigens Tumor cells Tumor Escape - genetics tumor immune evasion Tumor necrosis factor Tumor necrosis factor-TNF Tumors γ-Interferon United States Japan China United States > US ANGPTL2 MHC-I PRC2 tumor immune evasion H3K27me3
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Summary:	Loss or downregulation of major histocompatibility complex class I (MHC‐I) contributes to tumor immune evasion. We previously demonstrated that angiopoietin‐like protein 2 (ANGPTL2) promotes tumor progression using a Xp11.2 translocation renal cell carcinoma (tRCC) mouse model. However, molecular mechanisms underlying ANGPTL2 tumor‐promoting activity in the tRCC model remained unclear. Here, we report that ANGPTL2 deficiency in renal tubular epithelial cells slows tumor progression in the tRCC mouse model and promotes activated CD8+ T‐cell infiltration of kidney tissues. We also found that Angptl2‐deficient tumor cells show enhanced interferon γ‐induced expression of MHC‐I and increased susceptibility to CD8+ T‐cell‐mediated anti‐tumor immune responses. Moreover, we provide evidence that the ANGPTL2‐α5β1 integrin pathway accelerates polycomb repressive complex 2‐mediated repression of MHC‐I expression in tumor cells. These findings suggest that ANGPTL2 signaling in tumor cells contributes to tumor immune evasion and that suppressing that signaling in tumor cells could serve as a potential strategy to facilitate tumor elimination by T‐cell‐mediated anti‐tumor immunity. The ANGPTL2–α5β1‐integrin pathway in tumor cells accelerates polycomb repressive complex 2‐mediated repressive histone modification at the major histocompatibility complex class I (MHC‐I) promoter via JARID2 induction, thereby attenuating interferon γ‐induced MHC‐I expression in tumor cells. As a result, tumor cells show reduced susceptibility to CD8+ T cell‐mediated anti‐tumor immune responses, allowing tumor progression. Our findings provide novel insight into mechanisms underlying tumor immune evasion.
Bibliography:	Tsuyoshi Kadomatsu and Chiaki Hara contributed equally to this work ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1574-7891 1878-0261
DOI:	10.1002/1878-0261.13490