Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer

Abstract

Previous studies found patients with POLE exonuclease domain mutations (EDMs) in targeted exons were related to significant better outcomes in stage II-III colorectal cancer (CRC). The detailed mutational profile of the entire POLE exonuclease domain, tumor mutation burden (TMB) and immune cell infiltration in POLE EDMs tumors, and the prognostic value of such mutations in stage II CRCs were largely unknown to us. This study was to clarify the characteristics, immune response and prognostic value of somatic POLE EDMs in stage II CRC. A total of 295 patients with stage II CRC were sequenced by next-generation sequencing with a targeted genetic panel. Simultaneous detection of the immune cells was conducted using a five-color immunohistochemical multiplex technique. The detailed molecular characteristics, tumor-infiltrating lymphocyte (TIL) and prognostic effect of POLE EDMs in stage II CRC were analyzed. For stage II CRCs, the POLE EDMs were detected in 3.1% of patients. Patients with POLE EDMs were more prone to be microsatellite instability-high (MSI-H) (33.3% vs 11.2%, p=0.043), younger at diagnosis (median 46 years vs 62 years, p<0.001) and more common at right-sided location (66.7% vs 23.1%; p=0.003). All patients with POLE EMDs were assessed as extremely high TMB, with a mean TMB of 200.8. Compared with other stage II CRCs, POLE EDMs displayed an enhanced intratumoral cytotoxic T cell response, evidenced by increased numbers of CD8+TILs and CD8A expression. Patients with stage II CRCs could be classified into three risk subsets, with significant different 5 years disease-free survival rates of 100% for POLE EDMs, 82.0% for MSI-H and 63.0% for MSS, p=0.013. In conclusion, characterized by a robust intratumoral T cell response, ultramutated POLE EDMs could be detected in a small subset of stage II CRCs with extremely high TMB. Patients with POLE EDMs had excellent outcomes in stage II CRCs, regardless of MSI status. Sequencing of all the exonuclease domain of POLE gene is recommended in clinical practice.

Targeting DNA Damage Repair for Immune Checkpoint Inhibition: Mechanisms and Potential Clinical Applications

“…These tumors with POLE proofreading mutations were more prone to be MSI-H and were assessed as extremely high TMB. Patients with POLE proofreading mutations had excellent outcomes, regardless of MSI status, suggesting that sequencing of all the exonuclease domains of POLE gene is recommended for patients with colorectal cancer (32). More prospective large-scale clinical trials are warranted to verify the predictive role of POLE/POLD1 mutations for ICI, especially those in the proofreading domain.…”

Prognostic and Predictive Cross-Roads of Microsatellite Instability and Immune Response to Colon Cancer

“…Therefore, the agreement of oncologists may not fulfill undisputed standards when they are challenged by decision in certain clinical settings. Accordingly, the discussion with patients about pros and cons of adjuvant chemotherapy remains part of the operative decision making in the management of high-risk stage II colon cancer, as defined by the one of followings: T4 lesions, bowel obstruction or perforation, less than 12 lymph nodes in the surgical specimen, and poorly differentiated histology [ 72 ]. Large vessel invasion, perineural and extramural vascular invasion also are considered high-risk features of recurrence [ 73 ].…”

Biomarkers in Immunotherapy-Based Precision Treatments of Digestive System Tumors

“…More significantly, so many variables could lead to TMB-high, for example, MSI-H, gene variations (TP53, RRM1, FANCE, and POLG, etc.). Notably, the patients with POLE exonuclease domain mutations (EDMs) are thought to have a better prognosis ( 83 ). And in another pan-tumor analysis, the scholars counted the prevalence of POLE/POLD variations among 47,721 cancer patients, 2.79 and 1.37%, respectively; and the TMB level in those with such mutations was obviously higher than those without mutations ( 84 ).…”