Increased intraepithelial CD3+ T-lymphocytes and high PD-L1 expression on tumor cells are associated with a favorable prognosis in esophageal squamous cell carcinoma and allow prognostic immunogenic subgrouping

Abstract

Esophageal squamous cell carcinoma (ESCC) is the most common esophageal cancer associated with poor prognosis and additional therapeutic strategies must be implemented to optimize ESCC treatment. Meanwhile, the important biologic role and potential prognostic and therapeutic implications of a tumors immunologic microenvironment (IM) have been recognized in various cancers.In order to investigate the contexture and the prognostic relevance of the IM in ESCC, we immunohistochemically evaluated the extent of overall/intraepithelial TILs (CD3+/CD8+) and of PD-1 / PD-L1 expression in a cohort of 125 therapy-naive ESCCs, additionally assessing PD-L1 copy number status via fluorescence in-situ hybridization.High intraepithelial CD3+ TILs (CD3ihigh) and high PD-L1 expression on tumor cells (PD-L1high) were each significantly associated with improved overall- (OS) (CD3+: p = 0.019; PD-L1: p = 0.028), disease specific- (DSS) (CD3+: p = 0.05; PD-L1: p = 0.006) and disease free survival (DFS) (CD3+: p = 0.009; PD-L1: p < 0.001). CD3ihigh- and PD-L1high cases were significantly associated with one another (p < 0.001). Subgrouping of ESCC revealed decreased OS (p = 0.031), DSS (p = 0.012) and DFS (p < 0.001) for CD3ilow/PD-L1low cancers.Our data not only associate CD3ihigh- and PD-L1high ESCC with a beneficial outcome, but also demonstrate PD-L1high- and CD3ihigh status to be closely intertwined. Furthermore, our study demarcates a prognostically unfavorable, “non-immunoreactive” CD3ilow / PD-L1low ESCC-subgroup, potentially forming the basis for an immune-based stratification of ESCC.

Significance of Druggable Targets (PD-L1, KRAS, BRAF, PIK3CA, MSI, and HPV) on Curatively Resected Esophageal Squamous Cell Carcinoma

“…The univariate and multivariate analyses of therapy-naive tumors revealed that PD-L1-positive ESCC was associated with favorable OS and DFS. This result concurred with that of previous studies that demonstrated favorable prognosis of PD-L1 expression in surgically resected ESCCs without preoperative or neoadjuvant treatment [21][22][23]26]. In this study, high PD-L1 expression was prevalent among light or nonsmoker patients without lymph node metastasis and with high TILs.…”

“…Previously, several studies have reported that the frequencies of tumor cells exhibiting PD-L1 expression in ESCC range from 18.4-79.7%, which might be attributable to the differences in the antibodies used, interpretation criteria, specimen types affected by neoadjuvant therapy, and the geographic or racial characteristics [18][19][20][21][22][23][24]. In this study, PD-L1-positive tumors were observed in 35.9% of cases, which is highly consistent with a previous Korean population-based study (33.5%) [15].…”

Prognostic Implications of Infiltrating T Cells Within Tumors for Patients With Esophageal Squamous Cell Carcinoma: A Retrospective Cohort Study

“…Indeed, it has been reported that in ltrating bystander CD8 + T cells, which do not recognize tumor antigens and thus have no ability to kill neoplastic cells, exist in human lung and colorectal tumors. 21 For in ltrating CD3 + T cells, our results are consistent with the only available study 19 for ESCC. Both studies demonstrate that CD3 + T cell in ltration is an independent favourable prognostic factor.…”

“…For in ltrating CD8 + T cells, our results are consistent with a previous study, 19 but inconsistent with two other studies. 16,17 This inconformity suggests that in ltrating CD8 + T cells in esophageal tumors include different functional subgroups that are unable to be solely identi ed by IHC.…”

“…A recent study 18 also veri ed the favorable prognostic implication of CD8 + T cell in ltration. However, another study 19 indicated that CD8 + T cells in ltration does not provide prognostic information for ESCC patients. Nevertheless, these results need to be validated in more extensive ESCC patients.…”