5723: Inactivation of DNA repair triggers neoantigen generation and impairs tumor growth !

Genetic dissection of DNA damage response pathways reveals divergent modulation of PD-1 blockade response in colorectal cancer

Although MSI-H/dMMR colorectal cancers and the rarer subset with pathogenic POLE exonuclease domain mutations can benefit from immune checkpoint blockade, MSS colorectal cancer remains largely refractory, raising the question of whether other DNA damage response defects may also confer sensitivity to immunotherapy. Her...

Mechanism of neoantigen generation and advances in neoantigen-based immunotherapies in colorectal cancer

This review outlines the molecular mechanisms driving neoantigen generation in CRC, including frameshift mutations, single-nucleotide variants, alternative RNA splicing, and circular RNA-derived epitopes, and evaluates neoantigen-directed therapeutic platforms, encompassing personalized neoantigen vaccines and adoptive...

treatment alters mismatch repair and boosts mutational burden in tumor and blood of colorectal cancer patients

Induced mismatch repair deficiency: a hypothesis for the transient and reversible sensitization of mismatch repair-proficient tumors to Immune checkpoint blockade

Immune checkpoint blockade (ICB) has transformed the treatment landscape of multiple malignancies, producing durable responses and long-term survival in subsets of patients with advanced cancer. However, the clinical benefit of ICB remains largely restricted to tumors displaying pre-existing immune activation, high tum...

Mechanisms of immune resistance in microsatellite-stable colorectal cancer

Microsatellite-stable (MSS) colorectal cancer (CRC) accounts for approximately 85% of all CRC cases and exhibits limited responsiveness to immune checkpoint inhibitors (ICIs), representing a major challenge in current cancer immunotherapy. At the tumor-cell intrinsic level, low tumor mutational burden (TMB), impaired n...

Abstract B010: ELUCIDATING DNA DAMAGE REPAIR SIGNALING AND THERAPEUTIC VULNERABILITIES ACTIVATED BY TRANSPOSASE-DERIVED PGBD5

One hallmark of pediatric tumors is their low mutational burden, which contrasts with adult tumors, where cancer-causing mutations often accumulate over decades of DNA replication and environmental exposure. This raises the question of how such mutations arise in young patients. We have proposed that developmental mu...