PGRN inhibits CD8<SUP>+</SUP>T cell recruitment and promotes breast cancer progression by up-regulating ICAM-1 on TAM

作者全名："Zhou, Ting; Qian, Husun; Zhang, Dian; Fang, Wenli; Yao, Mengli; Shi, He; Chen, Tingmei; Chai, Chengsen; Guo, Bianqin"

作者地址："[Zhou, Ting; Qian, Husun; Zhang, Dian; Fang, Wenli; Yao, Mengli; Shi, He; Chen, Tingmei; Chai, Chengsen] Chongqing Med Univ, Coll Lab Med, Key Lab Clin Lab Diagnost, Minist Educ, Chongqing 400016, Peoples R China; [Guo, Bianqin] Chongqing Univ, Canc Hosp, Chongqing Key Lab Translat Res Canc Metastasis & I, Chongqing 400030, Peoples R China"

通信作者："Chai, CS (通讯作者)，Chongqing Med Univ, Coll Lab Med, Key Lab Clin Lab Diagnost, Minist Educ, Chongqing 400016, Peoples R China.; Guo, BQ (通讯作者)，Chongqing Univ, Canc Hosp, Chongqing Key Lab Translat Res Canc Metastasis & I, Chongqing 400030, Peoples R China."

来源：CANCER IMMUNOLOGY IMMUNOTHERAPY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001195485600003

JCR分区：Q1

影响因子：4.6

年份：2024

卷号：73

期号：5

开始页：　

结束页：　

文献类型：Article

关键词：Breast cancer (BCa); Progranulin (PGRN); Tumor-associated macrophages (TAMs); Programmed cell death protein 1 (PD-1); Intercellular cell adhesion molecule-1 (ICAM-1)

摘要："Background Tumor microenvironment actually reduces antitumor effect against the immune attack by exclusion of CD8(+)T cells. Progranulin (PGRN) is a multifunctional growth factor with significant pathological effects in multiple tumors; however, its role in immunity evasion of breast cancer (BCa) is not completely understood. Methods We depleted GRN (PGRN gene) genetically in mice or specifically in PY8119 murine BCa cell line, and mouse models of orthotopic or subcutaneous transplantation were used. Chimeric mice-deficient of PGRN (Grn(-/-)) in bone marrow (BM) compartment was also generated. Association of PGRN expression with chemokine production or BCa development was investigated by histological and immunological assays. Results We found PGRN was involved in exhaustion of cytotoxic CD8(+)T cell in BCa with the increasing expressions of M2 markers and intercellular cell adhesion molecule-1 (ICAM-1) on macrophages. Specifically, ablation of PGRN in PY8119 cells reduced tumor burden, accompanied by the infiltrating of cytotoxic CD8(+)T cells into tumor nests. Moreover, our result revealed that blockade of PD-1 in PGRN-depleted tumors exhibited better antitumor effect in vivo and significantly decreased tumor burden. Conclusion These findings suggest that inhibition of PGRN may act as a potential immune-therapeutic strategy by recovering infiltration of CD8(+)T cell in BCa tissue and thereby enhancing the response to anti-PD-1 therapy."

基金机构：National Natural Science Foundation of China

基金资助正文：We would like to thank Dr. Shifang Dong from Pediatric Research Institute of Children's Hospital of Chongqing Medical University for flow cytometry guidance.