Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2026
Differences in T-cell Densities and Neighborhood Patterns in Human Colorectal Adenomas and Sessile Serrated Lesions.
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Seal Souvik, Fanning Lauren R, Bagley Evan, Bookhout Christine, Barry Elizabeth L, O'Quinn Elizabeth C, Snover Dale C, Lewin David N, Guglietta Silvia, Kourtidis Antonis, Shrubsole Martha J, Baron John A, Mackenzie Todd A, Alekseyenko Alexander V, Wallace Kristin
Аннотация
BACKGROUND: T-cell responses influence recurrence and survival in colorectal cancer. T-cell subset distributions vary by molecular phenotype and anatomic location, shaping cytotoxic or immune-cold tumor immune microenvironments. However, the T-cell contexture and their spatial proximities within preinvasive lesions are not well characterized.
METHODS: We analyzed sessile serrated lesions (SSL), tubulovillous/villous adenomas (TV), and tubular adenomas (TA) from 3 studies (N = 120). Whole-slide multiplex immunofluorescence was used to quantify 8 T-cell subsets [CD4+, CD8+, helper T (Th) 1 (CD4+TBX21+), Th17 (CD4+RORC+), regulatory T cells (Treg; CD4+FOXP3+), Tc1 (CD8+TBX21+), Tc17 (CD8+RORC+), and TcTreg (CD8+FOXP3+)]. Densities were compared by histology using a generalized linear mixed model with a negative binomial distribution, including an offset for total cell area and adjusting for age, sex, anatomic location, and lesion size. Nearest neighbor (NN) analyses assessed spatial proximities of T-cell pairs across lesion types.
RESULTS: TAs and SSLs had higher CD4+ and CD8+ T-cell densities than TVs (q <0.05). Compared with TVs, TAs also had higher Th17 cell densities, whereas SSLs showed a trend toward lower Treg densities (q = 0.06). NN analysis showed greater Treg clustering in TVs than in SSLs and TAs. In contrast, TA versus SSL comparisons demonstrated predominant CD4+ clustering with Th17, Th1, and CD8+ subsets.
CONCLUSIONS: TVs exhibited lower T-cell densities and greater Treg clustering, consistent with an immune-cold environment. SSLs and TAs were more immune-infiltrated than TVs, but TAs had higher inflammation and CD4+-dominant clustering, suggesting stronger helper coordination.
IMPACT: Preinvasive lesions demonstrate immune and spatial heterogeneity which may have implications for primary or secondary prevention.
METHODS: We analyzed sessile serrated lesions (SSL), tubulovillous/villous adenomas (TV), and tubular adenomas (TA) from 3 studies (N = 120). Whole-slide multiplex immunofluorescence was used to quantify 8 T-cell subsets [CD4+, CD8+, helper T (Th) 1 (CD4+TBX21+), Th17 (CD4+RORC+), regulatory T cells (Treg; CD4+FOXP3+), Tc1 (CD8+TBX21+), Tc17 (CD8+RORC+), and TcTreg (CD8+FOXP3+)]. Densities were compared by histology using a generalized linear mixed model with a negative binomial distribution, including an offset for total cell area and adjusting for age, sex, anatomic location, and lesion size. Nearest neighbor (NN) analyses assessed spatial proximities of T-cell pairs across lesion types.
RESULTS: TAs and SSLs had higher CD4+ and CD8+ T-cell densities than TVs (q <0.05). Compared with TVs, TAs also had higher Th17 cell densities, whereas SSLs showed a trend toward lower Treg densities (q = 0.06). NN analysis showed greater Treg clustering in TVs than in SSLs and TAs. In contrast, TA versus SSL comparisons demonstrated predominant CD4+ clustering with Th17, Th1, and CD8+ subsets.
CONCLUSIONS: TVs exhibited lower T-cell densities and greater Treg clustering, consistent with an immune-cold environment. SSLs and TAs were more immune-infiltrated than TVs, but TAs had higher inflammation and CD4+-dominant clustering, suggesting stronger helper coordination.
IMPACT: Preinvasive lesions demonstrate immune and spatial heterogeneity which may have implications for primary or secondary prevention.