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Supplementary Data from Intertumoral Heterogeneity of CD3+ and CD8+ T-Cell Densities in the Microenvironment of DNA Mismatch-Repair–Deficient Colon Cancers: Implications for Prognosis

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posted on 2023-03-31, 21:27 authored by Harry H. Yoon, Qian Shi, Erica N. Heying, Andrea Muranyi, Joerg Bredno, Faith Ough, Azita Djalilvand, June Clements, Rebecca Bowermaster, Wen-Wei Liu, Michael Barnes, Steven R. Alberts, Kandavel Shanmugam, Frank A. Sinicrope

Figure S1 Study flow of N0147 patient tumor samples Figure S2 Heterogeneity of lymphocytic infiltrate between patients in mismatch repair deficient (dMMR) and proficient (pMMR) tumors. The distribution of T-cell densities (score 0-100) are shown as follows: (a) CD3+ in the core of the tumor, (b) CD8+ at the invasive margin, (c) CD8+ in the core of the tumor. For each T-cell subtype, density of tumor infiltration was higher in dMMR vs pMMR tumors (each p <.001).

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National Cancer Institutes of Health

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ARTICLE ABSTRACT

Colorectal cancers with deficient DNA mismatch repair (dMMR) are presumed to uniformly have dense lymphocytic infiltration that underlies their favorable prognosis and is critical to their responsiveness to immunotherapy, as compared with MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors. CD3+ and CD8+ T-cell densities were quantified at the invasive margin (IM) and tumor core (CT) in 561 stage III colon cancers (dMMR, n = 278; pMMR, n = 283) from a phase III adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis. Although CD3+ and CD8+ T-cell densities in the tumor microenvironment were higher in dMMR versus pMMR tumors overall, intertumoral heterogeneity in densities between tumors was significantly higher by 30% to 88% among dMMR versus pMMR cancers (P < 0.0001 for all four T-cell subtypes [CD3+IM, CD3+CT, CD8+IM, CD8+CT]). A substantial proportion of dMMR tumors (26% to 35% depending on the T-cell subtype) exhibited T-cell densities as low as that in the bottom half of pMMR tumors. All four T-cell subtypes were prognostic in dMMR with CD3+IM being the most strongly prognostic. Low (vs. high) CD3+IM was independently associated with poorer OS among dMMR (HR, 4.76; 95% confidence interval, 1.43–15.87; P = 0.0019) and pMMR tumors (P = 0.0103). Tumor-infiltrating T-cell densities exhibited greater intertumoral heterogeneity among dMMR than pMMR colon cancers, with CD3+IM providing robust stratification of both dMMR and pMMR tumors for prognosis. Potentially, lower T-cell densities among dMMR tumors may contribute to immunotherapy resistance.

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