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

Abstract

Background: 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 to MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors. Experimental Design: 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 3 adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis. Results: While CD3+ and CD8+ T-cell densities in the tumor microenvironment were higher in dMMR vs pMMR tumors overall, inter-tumoral heterogeneity in densities between tumors was significantly higher by 30–88% among dMMR vs pMMR cancers (P<.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% CI 1.43–15.87]; P=.0019) and pMMR tumors (P=.0103). Conclusions: Tumor-infiltrating T-cell densities exhibited greater inter-tumoral 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.

Mismatch Repair Status of Gastric Cancer and Its Association with the Local and Systemic Immune Response

“…As noted, there were several studies for the densities of stromal TILs at the invasive margin in colorectal cancer. The density of each subset of T cells is significantly differed according to location, and lower densities of CD3+ and CD8+ T cells at invasive margin was associated with shorter OS [33,34]. Unlike in colorectal cancer, the number of poorly cohesive carcinomas is high in stomach cancer.…”

Analysis of tumor microenvironmental features to refine prognosis by T, N risk group in patients with stage III colon cancer (NCCTG N0147) (Alliance)

“…Our finding that low TIL densities were significantly and independently associated with poorer DFS in the overall cohort is consistent with previous studies of TILs in CRC, including a population-based cohort, 18 case series of pooled tumor stages and variable treatment, 4 and data for CD3 þ and CD8 þ T cell densities and Immuno-score®. 4,5 We made the novel observation that TIL densities Figure 3. Relative contribution (percent) of (A) tumor-infiltrating lymphocytes (TILs), (B) tumor budding, and (C) the budding/TILs combined variable to diseasefree survival (DFS) in the overall cohort of patients with stage III colon cancer.…”

“…Strengths of our study include the large number of samestage patients with uniform treatment in a clinical trial and with long-term follow-up. In addition to TILs, intratumoral CD3 þ and CD8 þ T-cells 5 or the Immunoscore® (which uses a complex proprietary algorithm 4 ) has been shown to provide prognostic information in patients with colon cancer. However, analysis of TILs, as shown here, can be performed in routine histological tumor sections with concurrent determination of tumor budding.…”

“…3,4 TILs are enriched in tumors with deficient DNA mismatch repair (dMMR) in response to hypermutation and abundant mutation-specific neopeptides. 5 Tumor budding, defined as single or a cluster of tumor cells (four or fewer) at the tumor's invasive margin (IM), 6 has been linked to epithelialemesenchymal transition (EMT) and is intimately associated with stromal fibroblasts. 7 Tumor budding predicted lymph node metastasis in pT1 CRC and was associated with survival in patients with stage II CRC.…”

Artificial intelligence-guided tissue analysis combined with immune infiltrate assessment predicts stage III colon cancer outcomes in PETACC08 study

“…Concerning stage III CRC, contrasting data are available in the literature. While Laghi et al showed that CD3 infiltrates cannot be independently used to predict patient clinical outcomes,17 Sinicrope and Pagès, in two different clinical trials addressing FOLFOX-based adjuvant chemotherapy, demonstrated that CD3+ densities can independently predict patient outcomes in stage III CC 18 19…”