Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability–High Gastric Cancer

Abstract

Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers (GC) and associated with clinical response to anti-programmed death (PD)-1 antibodies. However, 50% of microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in advanced MSI-H GC patients and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with anti-tumor activity and prolonged progressionfree survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. Additionally, increase in PD-1 + CD8 + T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H GC and may inform development of strategies to enhance responsiveness.Research.

Prognostic Significance of Immune Checkpoints HLA-G/ILT-2/4 and PD-L1 in Colorectal Cancer

“…Though MSI-H, dMMR or TMB-high molecular phenotype varies among cancer patients, and not all patients with the MSI-H, dMMR or TMB-high phenotype respond to the ICIs therapy. In this context, exploration of mechanisms underlying resistance to ICIs is necessary (44,45). Moreover, due to many challenges, such as high variation in inter-assay precision and cut-off values associated with routine immunohistochemistry, multicolor flow cytometry can serve as a reliable and efficient alternative method.…”

Peripheral Blood-Based Biomarkers for Immune Checkpoint Inhibitors

“…Meanwhile, in patients with NSCLC who were pretreated with nivolumab, PD-1 + CD8 T cells at baseline were more frequently detected in patients with clinical benefit (CB) than in those with non-response (NR) [27]. Furthermore, a recent study showed that a higher percentage of circulating PD-1 + CD8 T cells at baseline was associated with a clinical benefit in patients with MSI-high gastric cancer treated with pembrolizumab [28].…”

Clinical Perspectives of Single-Cell RNA Sequencing

“…In a more recent study, Transcription Factor 7 (TCF7)-but not PDCD1 (PD-1 gene)-expression, was found to be a positive predictor of tumor regression in melanoma [63]. In MSI-high gastric cancer, a diverse T cell receptor (TCR) repertoire and the presence of early-to-intermediate activation status T cells in tumor tissues were found to be associated with an ICT response [68]. As T cell activation and exhaustion are confounding processes, exhaustion markers are good indicators of the presence of tumor-directed immunity; however, terminal differentiation of collective tumor-specific T cells in the exhausted state may adversely influence the ICT response.…”

“…The abundance of PD-1+ CD8+ T cells correlate with response and longer survival to PD-1 blockade. [68] Comparison between responders and non-responders provides critical information regarding patient stratification and the mechanism of action of ICT [69]. Characterization of post-treatment samples helps define the immune cell dynamics and state transitions [70].…”

“…Biomolecules 2021, 11, x FOR PEER REVIEW 9 of 18 diverse T cell receptor (TCR) repertoire and the presence of early-to-intermediate activation status T cells in tumor tissues were found to be associated with an ICT response [68].…”