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- Title
PGRN inhibits CD8<sup>+</sup>T cell recruitment and promotes breast cancer progression by up-regulating ICAM-1 on TAM.
- Authors
Zhou, Ting; Qian, Husun; Zhang, Dian; Fang, Wenli; Yao, MengLi; Shi, He; Chen, Tingmei; Chai, Chengsen; Guo, Bianqin
- Abstract
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.
- Subjects
BREAST cancer; CANCER invasiveness; PROGRANULIN; BONE marrow; MULTIPLE tumors; VASCULAR cell adhesion molecule-1
- Publication
Cancer Immunology, Immunotherapy, 2024, Vol 73, Issue 5, p1
- ISSN
0340-7004
- Publication type
Article
- DOI
10.1007/s00262-024-03655-z