Background: Colorectal cancers (CRC) with dMMR typically have abundant TILs indicating an enhanced host immune response. However, the prognostic impact of TILs identified by CD3⁺ and CD8⁺ T cells has not been adequately studied in dMMR tumors. While dMMR is considered a predictive biomarker for anti-PD-1 therapy in advanced CRC, ~60% of dMMR pts do not respond, which may be relevant in dMMR stage III where adjuvant PD-L1 blockade is being studied. We report the first evaluation of CD3⁺/CD8⁺ TILs with prognosis in dMMR tumors from a clinical trial cohort. Methods: CD3⁺ and CD8⁺ TILs at the invasive margin (IM) and central tumor (CT) were analyzed in 561 stage III colon cancers (dMMR n = 278; randomly selected pMMR n = 283) from a phase 3 trial of FOLFOX-based adjuvant therapy (N = 3270 [dMMR 376, pMMR 2894]). Median follow up was 6.3 y. Immunostaining was quantified by image analysis (0-100 scale). Associations with overall survival (OS) were evaluated by multivariable Cox regression. Results: Densities of CD3⁺ and CD8⁺ TILs were higher in dMMR vs pMMR tumors (P< .001), and were heterogeneous between pts in each MMR group. CD3⁺ IM was the strongest prognostic marker; the other markers (CD3⁺ CT, CD8⁺ IM, CD8⁺ CT), alone or combined, did not add further value. Among dMMR tumors, using an optimized cutpoint, 58% had low CD3⁺ IM, and these pts had significantly shorter OS v dMMR tumors with high CD3⁺ IM, independent of covariates. See Table for full results. OS of dMMR tumors with low CD3⁺ IM was comparable to the overall pMMR cohort (n = 2611; P = .8). Pts with high CD3⁺ IM pMMR tumors had an OS similar to TIL-unselected dMMR tumors (n = 376; P = .3). Conclusions: CD3⁺ IM TILs can prognostically stratify pts with dMMR stage III colon cancer for OS. These findings of heterogeneity within dMMR may have implications for immunotherapy responsiveness in dMMR tumors.

Adjustments included T, N, grade, BRAF/KRAS, tumor side, age, smoking