GITR and TIGIT immunotherapy provokes divergent multi-cellular responses in the tumor microenvironment of gastrointestinal cancers.

Autor:	Sathe A; Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States., Ayala C; Division of Surgical Oncology, Department of Surgery, Stanford University, Stanford, CA, United States., Bai X; Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States., Grimes SM; Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States., Lee B; Division of Surgical Oncology, Department of Surgery, Stanford University, Stanford, CA, United States., Kin C; Division of Surgical Oncology, Department of Surgery, Stanford University, Stanford, CA, United States., Shelton A; Division of Surgical Oncology, Department of Surgery, Stanford University, Stanford, CA, United States., Poultsides G; Division of Surgical Oncology, Department of Surgery, Stanford University, Stanford, CA, United States., Ji HP; Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Mar 15. Date of Electronic Publication: 2023 Mar 15.
DOI:	10.1101/2023.03.13.532299
Abstrakt:	Understanding the cellular mechanisms of novel immunotherapy agents in the human tumor microenvironment ( TME ) is critical to their clinical success. We examined GITR and TIGIT immunotherapy in gastric and colon cancer patients using ex vivo slice tumor slice cultures derived from cancer surgical resections. This primary culture system maintains the original TME in a near-native state. We applied paired single-cell RNA and TCR sequencing to identify cell type specific transcriptional reprogramming. The GITR agonist was limited to increasing effector gene expression only in cytotoxic CD8 T cells. The TIGIT antagonist increased TCR signaling and activated both cytotoxic and dysfunctional CD8 T cells, including clonotypes indicative of potential tumor antigen reactivity. The TIGIT antagonist also activated T follicular helper-like cells and dendritic cells, and reduced markers of immunosuppression in regulatory T cells. Overall, we identified cellular mechanisms of action of these two immunotherapy targets in the patients' TME. Competing Interests: Conflict of interest statement: The authors declare no potential conflicts of interest.
Databáze:	MEDLINE
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