CD226^hiCD8⁺ T Cells Are a Prerequisite for Anti-TIGIT Immunotherapy

Area of Science:

• Immunology
• Cancer Biology
• T-cell Biology

Background:

• Clinical trials are investigating anti-TIGIT therapies, alone or with PD-1/PD-L1 blockade.
• The synergistic mechanisms of TIGIT blockade with existing immunotherapies remain unclear.

Purpose of the Study:

• To investigate the role of CD226 expression in CD8+ T-cell responses to anti-TIGIT therapy.
• To identify predictive biomarkers for anti-TIGIT efficacy.

Main Methods:

• Analysis of CD8+ T cells in tumor microenvironments based on CD226 expression.
• Assessment of T-cell functionality and phenotype.
• Evaluation of anti-TIGIT and CD226 agonist antibody effects.
• Investigation of mFOLFIRINOX treatment impact on T-cell populations and immunotherapy response.

Main Results:

• CD226lo CD8+ T cells exhibit an exhausted phenotype, while CD226hi CD8+ T cells show enhanced functionality and self-renewal.
• Anti-TIGIT treatment selectively targets CD226hi CD8+ T cells via CD226 phosphorylation.
• CD226 activation synergizes with TIGIT blockade, boosting CD8+ T-cell responses.
• mFOLFIRINOX increases CD226hi CD8+ T cells, potentiating anti-TIGIT and anti-PD-1 efficacy in pancreatic cancer.

Conclusions:

• CD226 serves as a predictive biomarker for cancer immunotherapy response.
• Elevated CD226hi CD8+ T-cell populations may enhance outcomes with anti-TIGIT therapy.