Abstract
Primary esophageal small cell carcinoma (PESCC) is a weakly prevalent but lethal malignancy with early metastasis and a poor prognosis. Currently, neither effective prognostic indicators nor curative therapies are available for PESCC. Immunotherapy has now evolved into one of the most promising therapies for cancer patients. Tumor-infiltrating immune cells which are integral to the tumor immune microenvironment (TIME) are recognized as highly important for prognosis prediction, while the responsiveness to immune checkpoint blockade may be subject to the features of TIME. In this study, we aim to identify the TIME and provide indication for the applicability of immune checkpoint therapy in PESCC. We found that PD-L1 expression was detected in 33.33% (27/81) of all the patients, mostly exhibiting a stroma-only pattern and that it was positively associated with tumor-infiltrating immune cells (CD4+, CD8+, and CD163+). In 74.07% of PD-L1-positive specimens, PD-L1+CD163+ cells were colocalized more with CD4+ than CD8+ T cells. 83.95% (68/81) of all the specimens were infiltrated with more CD4+ than CD8+ T cells. Further analysis showed FoxP3+ Tregs constituted 13-27% of the total CD4+ T cell population. The Kaplan-–Meier analysis indicated several factors that contribute to poor survival, including negative PD-L1 expression, rich CD4 expression, rich FoxP3 expression, a low CD8/CD4 ratio, and a high FoxP3/CD8 ratio. A nomogram model was constructed and showed good performance for survival prediction. These results highlight that a suppressive TIME contributes to poor survival of patients with PESCC. TIME analyses might be a promising approach to evaluate the possibility and effect of immune checkpoint-based immunotherapeutics in PESCC patients.
Highlights
Primary esophageal small cell carcinoma (PESCC) is a rare but fast-growing tumor that exhibits a neuroendocrine phenotype and accounts for 0.5-2.8% of all esophageal malignancies [1]
The diagnosis of PESCC in this study was confirmed by hematoxylin and eosin (H&E) staining and IHC staining for neuroendocrine markers, epithelial markers, or TTF1 and Ki67 (Figures S1 and S2)
We further explored the relationship between PD-L1+CD163+ tumorassociated macrophages (TAMs) and tumor-infiltrating lymphocyte (TIL) on the basis of a previous report that demonstrated the PDL1+ TAM is an ideal indicator for PD-1/PD-L1 blockade treatment [28]
Summary
Primary esophageal small cell carcinoma (PESCC) is a rare but fast-growing tumor that exhibits a neuroendocrine phenotype and accounts for 0.5-2.8% of all esophageal malignancies [1]. Clinical trials have demonstrated the effectiveness of pembrolizumab and nivolumab (PD-1 inhibitors) in small cell lung cancer (SCLC) patients [12,13,14]. The expression of PD-L1, as detected by immunohistochemical staining, is an important indicator for the use of PDL1/PD-1 inhibitors in patients with lung cancer and melanoma [15]. Growing evidence indicates that PDL1 as a single biomarker is not precise enough to predict the response to PD-L1/PD-1 inhibition. Other factors, such as tumor-infiltrating lymphocyte (TIL) subsets, need to be taken into consideration [16,17,18]. Most studies of PESCC are case reports focusing on individuals, and no systematic investigation of the PD-L1 expression pattern and immune cells within the TIME of PESCC has been reported
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