ESMO Congress 2024 | OncologyPRO

Abstract 15P

Background

PD-1/PD-L1 blockade combined with chemoradiotherapy putatively benefited patients with dMMR/MSI-H colorectal cancer. However, the effect of PD-L1 blockade plus chemoradiotherapy for pMMR/MSS rectal cancer remains unclear, and the mechanisms influencing therapeutic response need further exploration.

Methods

A phase II, open-labeled, study was conducted to evaluate the efficacy and safety of adding Atezolizumab (PD-L1 blockade) to neoadjuvant chemoradiotherapy in MSS locally advanced rectal cancer (LARC). All patients received long-course radiotherapy plus capecitabine followed by three 21-day cycles Atezolizumab and TME surgery. Single cell RNA sequencing was performed on surgical resection samples.

Results

Twelve patients were recruited with 100% R0 resection. 50% (n=6) of MPR rate was observed, 3 of these patients achieved pCR. Interestingly, the proportion of T cells in the non-MPR group was significantly higher than in the MPR group, particularly TIGIT+ CD8+ T cells. However, further analysis indicated that the T cells in the non-MPR group were functionally exhausted. Compared to the MPR group, the interaction between NECTIN2+ cancer-associated fibroblasts and TIGIT+ CD8+ T cells was significantly enhanced in the non-MPR group. Mechanistically, the NECTIN2-TIGIT interaction limit the cytotoxic response by CD8+ T cells through inhibition of cyclic GMP-AMP synthase (cGAS)-STING pathway. Moreover, addition of TIGIT blockade to PD-L1 blockade plus chemoradiotherapy significantly enhances the therapeutic efficacy in MSS rectal cancer in vitro and in vivo.

Conclusions

NECTIN2-TIGIT serves as a crucial immune checkpoint for the efficacy of PD-L1 blockade plus chemoradiotherapy in MSS locally advanced rectal cancer, and the supplementary application of TIGIT blockade presents a rational approach for an immunotherapeutic combination strategy.