Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 8, Issue 2, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2019-000422
Keywords
gastroenterology; tumours; immunology
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Funding
- National Natural Science Foundation of China (NSFC) [81872331, 81502457]
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Background Overexpression of programmed cell death protein 1 (PD-1) is linked to CD8+ T cell dysfunction and contributes to tumor immune escape. However, the prevalence and functional regulations of PD-1 expression on CD8+ T cells in human gastric cancer (GC) remain largely unknown. Methods Flow cytometry was performed to analyze the level, phenotype, functional and clinical relevance of PD-1+CD8+ T cells in GC patients. Peripheral blood CD8+ T cells were purified and subsequently exposed to culture supernatants from digested primary GC tumor tissues (TSN) in vitro for PD-1 expression and functional assays. Tumor responses to adoptively transferred TSN-stimulated CD8+ T cells or to the TSN-stimulated CD8+ T cell transfer combined with an anti-PD-1 antibody injection were measured in an in vivo xenograft mouse model. Results GC patients' tumors showed a significantly increased PD-1+CD8+ T cell infiltration. However, these GC-infiltrating PD-1+CD8+ T cells showed equivalent function to their PD-1-CD8+ counterparts and they did not predict tumor progression. High level of transforming growth factor-beta 1 (TGF-beta 1) in tumors was positively correlated with PD-1+CD8+ T cell infiltration, and in vitro GC-derived TGF-beta 1 induced PD-1 expression on CD8+ T cells via Smad3 signaling, whereas Smad2 signaling was involved in GC-derived TGF-beta 1-mediated CD8+ T cell dysfunction. Furthermore, GC-derived TGF-beta 1-mediated CD8+ T cell dysfunction contributed to tumor growth in vivo that could not be attenuated by PD-1 blockade. Conclusions Our data highlight that GC-derived TGF-beta 1 promotes PD-1 independent CD8+ T cell dysfunction. Therefore, restoring CD8+ T cell function by a combinational PD-1 and TGF-beta 1 blockade might benefit future GC immunotherapy.
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