Heterogeneity in the lymphocytic infiltration of deficient DNA mismatch repair colon cancers

TY - JOUR

T1 - Heterogeneity in the lymphocytic infiltration of deficient DNA mismatch repair colon cancers

AU - Yoon, Harry H.

AU - Sinicrope, Frank A.

N1 - Funding Information: While it is believed that an abundant lymphocytic infiltrate is almost uniformly present in CRCs with dMMR, we determined the potential for inter-tumoral heterogeneity in lymphocytic infiltration among dMMR colon cancers. Specifically, we quantified the density of CD3+ and CD8+ T cells at the invasive margin (tumor’s leading edge) and tumor center in 561 stage III colon cancers. We examined all dMMR tumors and a randomly selected subgroup of pMMR tumors from patients who received adjuvant FOLFOX-based chemotherapy in a phase III clinical trial sponsored by the U.S. National Cancer Institute (N0147) [1]. CD3+ is a pan-T cell marker and CD8+ is a marker of cytotoxic T cells. Consistent with prior data, we found that CD3+ and CD8+T-cell densities in the tumor microenvironment were higher in dMMR vs pMMR tumors overall. However, we unexpectedly observed that dMMR colon cancers demonstrated significantly greater inter-tumoral heterogeneity in the density of their lymphocytic infiltrate compared to pMMR tumors (Figure 1). Inter-tumoral heterogeneity in densities was significantly increased by 30-88% among dMMR vs pMMR cancers (P < .0001 for all four T-cell subtypes [CD3+ or CD8+ at the invasive margin or tumor center]). Importantly, a substantial proportion of dMMR tumors (26% to 35% depending on T-cell subtype) exhibited T-cell densities as low as those found in the bottom half of densities within pMMR tumors. Stated differently, approximately one-third of dMMR colon cancers do not have a rich lymphocyte infiltrate. A number of factors could underlie the inter-tumoral heterogeneity among dMMR tumors including differences in the overall mutation burden, unstable microsatellites, or variability in neoantigen profiles [2]. In a recent study, dMMR CRCs from patients with Lynch Syndrome had a higher density of intratumoral CD3+ T cells (vs sporadic dMMR) in association with increased somatic mutations and higher neoantigen burden [3].

PY - 2018/12/1

Y1 - 2018/12/1

KW - Colon stage III

KW - Heterogeneity

KW - Mismatch repair

KW - Prognosis

KW - Tumor infiltrating lymphocyte

UR - http://www.scopus.com/inward/record.url?scp=85058042323&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058042323&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.26395

DO - 10.18632/oncotarget.26395

M3 - Editorial

C2 - 30613356

AN - SCOPUS:85058042323

SN - 1949-2553

VL - 9

SP - 36722

EP - 36723

JO - Oncotarget

JF - Oncotarget

IS - 95

ER -