Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Sathe A

PROVIDER: S-EPMC10054933 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Sathe Anuja A Ayala Carlos C Bai Xiangqi X Grimes Susan M SM Lee Byrne B Kin Cindy C Shelton Andrew A Poultsides George G Ji Hanlee P HP

bioRxiv : the preprint server for biology 20230315

Understanding the cellular mechanisms of novel immunotherapy agents in the human tumor microenvironment (<b>TME</b>) is critical to their clinical success. We examined GITR and TIGIT immunotherapy in gastric and colon cancer patients using <i>ex vivo</i> 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 transcriptiona ...[more]

PMID: 36993756

Similar Datasets

Project description:BackgroundUnderstanding the mechanistic effects of novel immunotherapy agents is critical to improving their successful clinical translation. These effects need to be studied in preclinical models that maintain the heterogenous tumor microenvironment (TME) and dysfunctional cell states found in a patient's tumor. We investigated immunotherapy perturbations targeting co-stimulatory molecule GITR and co-inhibitory immune checkpoint TIGIT in a patient-derived ex vivo system that maintains the TME in its near-native state. Leveraging single-cell genomics, we identified cell type-specific transcriptional reprogramming in response to immunotherapy perturbations.MethodsWe generated ex vivo tumor slice cultures from fresh surgical resections of gastric and colon cancer and treated them with GITR agonist or TIGIT antagonist antibodies. We applied paired single-cell RNA and TCR sequencing to the original surgical resections, control, and treated ex vivo tumor slice cultures. We additionally confirmed target expression using multiplex immunofluorescence and validated our findings with RNA in situ hybridization.ResultsWe confirmed that tumor slice cultures maintained the cell types, transcriptional cell states and proportions of the original surgical resection. The GITR agonist was limited to increasing effector gene expression only in cytotoxic CD8 T cells. Dysfunctional exhausted CD8 T cells did not respond to GITR agonist. In contrast, the TIGIT antagonist increased TCR signaling and activated both cytotoxic and dysfunctional CD8 T cells. This included cells corresponding to TCR clonotypes with features 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.ConclusionsWe identified novel cellular mechanisms of action of GITR and TIGIT immunotherapy in the patients' TME. Unlike the GITR agonist that generated a limited transcriptional response, TIGIT antagonist orchestrated a multicellular response involving CD8 T cells, T follicular helper-like cells, dendritic cells, and regulatory T cells. Our experimental strategy combining single-cell genomics with preclinical models can successfully identify mechanisms of action of novel immunotherapy agents. Understanding the cellular and transcriptional mechanisms of response or resistance will aid in prioritization of targets and their clinical translation.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets