Mayo Clinic, Rochester, MN
Harry H. Yoon , Qian Shi , Erica N Heying , Andrea Muranyi , Faith Ough , Azita Djalilvand , June Clements , Rebecca Bowermaster , Wen-Wei Liu , Michael Barnes , Steven R. Alberts , Kandavel Shanmugam , Frank A. Sinicrope
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.
CD3+ IM (cutpoint) | n (%) | HRadj | Padj | 5y OS rate | |
---|---|---|---|---|---|
dMMR | Per 10-unit decrease | 1.1 | .015 | ||
High (≥ 49) | 111 (42) | Ref | .026 | 84% | |
Low (≤ 48) | 167 (58) | 2.1 | 70% | ||
pMMR | Per 10-unit decrease | 1.2 | .009 | ||
High (≥ 21) | 177 (63) | Ref | .073 | 83% | |
Low (≤ 20) | 106 (37) | 1.7 | 73% |
Adjustments included T, N, grade, BRAF/KRAS, tumor side, age, smoking
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