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衰老肿瘤细胞在结直肠癌中构建细胞因子屏障。

Senescent Tumor Cells Build a Cytokine Shield in Colorectal Cancer.

作者信息

Choi Yong Won, Kim Young Hwa, Oh Seung Yeop, Suh Kwang Wook, Kim Young-Sam, Lee Ga-Yeon, Yoon Jung Eun, Park Soon Sang, Lee Young-Kyoung, Park Yoo Jung, Kim Hong Seok, Park So Hyun, Kim Jang-Hee, Park Tae Jun

机构信息

Department of Biochemistry and Molecular Biology Ajou University School of Medicine Suwon 16499 Korea.

Department of Hematology-Oncology Ajou University School of Medicine Suwon 16499 Korea.

出版信息

Adv Sci (Weinh). 2021 Jan 4;8(4):2002497. doi: 10.1002/advs.202002497. eCollection 2021 Feb.

DOI:10.1002/advs.202002497
PMID:33643790
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7887594/
Abstract

Cellular senescence can either support or inhibit cancer progression. Here, it is shown that intratumoral infiltration of CD8 T cells is negatively associated with the proportion of senescent tumor cells in colorectal cancer (CRC). Gene expression analysis reveals increased expression of C-X-C motif chemokine ligand 12 (CXCL12) and colony stimulating factor 1 (CSF1) in senescent tumor cells. Senescent tumor cells inhibit CD8 T cell infiltration by secreting a high concentration of CXCL12, which induces a loss of CXCR4 in T cells that result in impaired directional migration. CSF1 from senescent tumor cells enhance monocyte differentiation into M2 macrophages, which inhibit CD8 T cell activation. Neutralization of CXCL12/CSF1 increases the effect of anti-PD1 antibody in allograft tumors. Furthermore, inhibition of CXCL12 from senescent tumor cells enhances T cell infiltration and results in reducing the number and size of tumors in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC. These findings suggest senescent tumor cells generate a cytokine barrier protecting nonsenescent tumor cells from immune attack and provide a new target for overcoming the immunotherapy resistance of CRC.

摘要

细胞衰老既可以支持也可以抑制癌症进展。在此研究中发现，结直肠癌（CRC）中CD8 T细胞的肿瘤内浸润与衰老肿瘤细胞的比例呈负相关。基因表达分析显示，衰老肿瘤细胞中C-X-C基序趋化因子配体12（CXCL12）和集落刺激因子1（CSF1）的表达增加。衰老肿瘤细胞通过分泌高浓度的CXCL12抑制CD8 T细胞浸润，CXCL12会导致T细胞中CXCR4丢失，从而损害定向迁移。衰老肿瘤细胞分泌的CSF1会增强单核细胞向M2巨噬细胞的分化，进而抑制CD8 T细胞的活化。中和CXCL12/CSF1可增强同种异体移植肿瘤中抗PD1抗体的效果。此外，抑制衰老肿瘤细胞分泌的CXCL12可增强T细胞浸润，并减少由氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的CRC中的肿瘤数量和大小。这些发现表明，衰老肿瘤细胞产生了一种细胞因子屏障，保护非衰老肿瘤细胞免受免疫攻击，并为克服CRC的免疫治疗耐药性提供了新的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/cac75b803644/ADVS-8-2002497-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/a197b03c62c7/ADVS-8-2002497-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/05d1544a4740/ADVS-8-2002497-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/d561c9841843/ADVS-8-2002497-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/83c4e42e3ed7/ADVS-8-2002497-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/9fcce443bc28/ADVS-8-2002497-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/4beed8d3a683/ADVS-8-2002497-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/1ece441b9baf/ADVS-8-2002497-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/cac75b803644/ADVS-8-2002497-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/a197b03c62c7/ADVS-8-2002497-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/05d1544a4740/ADVS-8-2002497-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/d561c9841843/ADVS-8-2002497-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/83c4e42e3ed7/ADVS-8-2002497-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/9fcce443bc28/ADVS-8-2002497-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/4beed8d3a683/ADVS-8-2002497-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/1ece441b9baf/ADVS-8-2002497-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a3e/7887594/cac75b803644/ADVS-8-2002497-g008.jpg

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