Chimeric Antigen Receptor T Cell Therapy Targeting Epithelial Cell Adhesion Molecule in Gastric Cancer: Mechanisms of
Yanping Yang1,2, Raymond Louie3, Janusz Puc4
1Department of Radiology, Houston Methodist Research Institute, Houston, TX 77030, USA.
Abstract:
Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen that is frequently overexpressed in various carcinomas. We have developed chimeric antigen receptor (CAR) T cells specifically targeting EpCAM for the treatment of gastric cancer. This study sought to unravel the precise mechanisms by which tumors evade immune surveillance and develop resistance to CAR T cell therapy. Through a combination of whole-body CAR T cell imaging and single-cell multiomic analyses, we uncovered intricate interactions between tumors and tumor-infiltrating lymphocytes (TILs). In a gastric cancer model, tumor-infiltrating CD8 T cells exhibited both cytotoxic and exhausted phenotypes, while CD4 T cells were mainly regulatory T cells. A T cell receptor (TCR) clonal analysis provided evidence of CAR T cell proliferation and clonal expansion within resistant tumors, which was substantiated by whole-body CAR T cell imaging. Furthermore, single-cell transcriptomics showed that tumor cells in mice with refractory or relapsing outcomes were enriched for genes involved in major histocompatibility complex (MHC) and antigen presentation pathways, interferon-γ and interferon-α responses, mitochondrial activities, and a set of genes (e.g., CD74, IDO1, IFI27) linked to tumor progression and unfavorable disease prognoses. This research highlights an approach that combines imaging and multiomic methodologies to concurrently characterize the evolution of tumors and the differentiation of CAR T cells.
Insights
Chimeric antigen receptor (CAR) T cells targeting EpCAM show promise for gastric cancer. Tumors evade therapy through complex immune interactions and genetic changes, revealing new therapeutic targets.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Epithelial cell adhesion molecule (EpCAM) is a tumor antigen overexpressed in carcinomas.
- Chimeric antigen receptor (CAR) T cells targeting EpCAM are being developed for gastric cancer treatment.
Purpose of the Study:
- To investigate mechanisms of tumor immune evasion and resistance to CAR T cell therapy.
- To characterize tumor-infiltrating lymphocytes (TILs) and tumor cell genetic alterations in response to CAR T cell therapy.
Main Methods:
- Whole-body CAR T cell imaging was used to track CAR T cell distribution and expansion.
- Single-cell multiomic analyses, including transcriptomics and T cell receptor (TCR) clonal analysis, were performed.
- Gastric cancer models were utilized to study tumor-immune interactions.
Main Results:
- Tumor-infiltrating CD8 T cells showed cytotoxic and exhausted phenotypes; CD4 T cells were primarily regulatory T cells.
- CAR T cell proliferation and clonal expansion were observed in resistant tumors.
- Tumor cells in refractory/relapsing models were enriched for genes in MHC/antigen presentation, interferon responses, and mitochondrial activity, including CD74, IDO1, and IFI27.
Conclusions:
- Combined imaging and multiomic approaches can elucidate tumor evolution and CAR T cell differentiation.
- Understanding these mechanisms is crucial for overcoming resistance to CAR T cell therapy in gastric cancer.
More Related Videos
09:56A Nonviral Approach to Generate Transient Chimeric Antigen Receptor T Cells Using mRNA for Cancer Immunotherapy
Published on: February 21, 2025
08:04In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
Related Concept Videos
02:38Mitogens and the Cell Cycle
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:27Tumor Immunotherapy
02:17The Tumor Microenvironment
02:56Treatment Resistant Cancers