Immune profiling of microsatellite instability-high and polymerase ε (POLE)-mutated metastatic colorectal tumors identifies predictors of response to anti-PD-1 therapy

Abstract

Higher densities of CD8+ TILs, PD-1-expressing CD8+ TILs, and tumor-infiltrating immune cells with a Th1 phenotype in the TME may predict response to checkpoint inhibitors in MSI-H and -mutated mCRC.

Complete and Prolonged Response to Immune Checkpoint Blockade in POLE-Mutated Colorectal Cancer

“…Previous reports include two endometrial cancers 12,13 and a single colorectal cancer described at 4 and 12 months of follow-up. 14,15 The four responsive tumors, including the tumor in this report, displayed mutations in the exonuclease domain of POLE ( Fig 1D) and ultra-high mutation burdens (greater than 100 mutations/ Mb, ie, more than 5-fold greater than the median TMB reported for MSI and POLE-mutated tumors 17 [ Fig 1C]). By contrast, the responsive tumors were inconsistent in PD-L1 expression ( Fig 1D).…”

“…Two colorectal cancers with the p.P286R mutation showed progressive and stable disease after 1 and more than 10 months of follow-up. 15 Both cases showed low levels of CD8 + TILs. In fact, in a cohort of five MSI tumors and three POLE-mutated tumors, high levels of CD8 + TILs occurred in all four patients who experienced response and none of the four patients who did not experience response (P = .0007).…”

Exploiting DNA repair defects in colorectal cancer

“…Recent studies have shown that MSI tumor cells are responsive to PD‐1 and CTLA‐4 immune blockade (Germano et al ., ; Le et al ., ; Luksza et al ., ; McGranahan et al ., ). In one study, patients with higher TILs and PD‐L1 expression responded to checkpoint blockade better compared with patients with lower PD‐L1 expression, suggesting that this phenotype can be used as a predictor of therapy response (Wang et al ., ). A 2017 Phase II clinical trial of nivolumab, a PD‐L1 immune checkpoint inhibitor, in patients with MMRd and MSI‐H CRC who had received at least three rounds of prior therapy and were no longer responsive to first‐line treatments found that this therapy provided durable response and disease control in these patients.…”

Systemic treatment for metastatic colorectal cancer in the era of precision medicine

“…Exonuclease domains of DNA polymerase δ ( POLD ) and Polymerase ɛ ( POLE ) are critical components of the normal DNA replication process and provide an essential proofreading function. Mutations in POLE and POLD occur in approximately 1% of colorectal cancers and have been associated with an ulltramutated tumor status (very high tumor mutation burden) and increased tumor PD‐L1 expression and infiltration with cytotoxic lymphocytes . These tumors are associated with a decreased risk of recurrence and are underrepresented in the setting of metastatic disease in comparison to earlier stages of CRC .…”

“…These tumors are associated with a decreased risk of recurrence and are underrepresented in the setting of metastatic disease in comparison to earlier stages of CRC . Emerging clinical data support significant activity of the anti‐PD‐1 monocolonal antibody in this population, with complete and protracted partial responses being reported in a series of case reports . These patients should be considered for immunotherapy with PD‐1/PD‐L1 targeted agents, especially in chemoresistant settings.…”