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Pre-treatment tumor-infiltrating T cells influence response to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma.

ABSTRACT: Esophageal adenocarcinoma (EAC) is a disease with dismal treatment outcomes. Response to neoadjuvant chemoradiation (CRT) varies greatly. Although the underlying mechanisms of CRT resistance are not identified, accumulating evidence indicates an important role for local antitumor immunity. To explore the immune microenvironment in relation to response to CRT we performed an in-depth analysis using multiplex immunohistochemistry, flow cytometry and mRNA expression analysis (NanoString) to generate a detailed map of the immunological landscape of pretreatment biopsies as well as peripheral blood mononuclear cells (PBMCs) of EAC patients. Response to CRT was assessed by Mandard's tumor regression grade (TRG), disease-free- and overall survival. Tumors with a complete pathological response (TRG 1) to neoadjuvant CRT had significantly higher tumor-infiltrating T cell levels compared to all other response groups (TRG 2-5). These T cells were also in closer proximity to tumor cells in complete responders compared to other response groups. Notably, immune profiles of near-complete responders (TRG 2) showed more resemblance to non-responders (TRG 3-5) than to complete responders. A high CD8:CD163 ratio in the tumor was associated with an improved disease-free survival. Gene expression analyses revealed that T cells in non-responders were Th2-skewed, while complete responders were enriched in cytotoxic immune cells. Finally, complete responders were enriched in circulating memory T cells. preexisting immune activation enhances the chance for a complete pathological response to neoadjuvant CRT. This information can potentially be used for future patient selection, but also fuels the development of immunomodulatory strategies to enhance CRT efficacy.

SUBMITTER: Goedegebuure RSA

PROVIDER: S-EPMC8344794 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNeoadjuvant chemoradiotherapy (neo-CRT) plus surgery has greatly improved the prognosis of locally advanced esophageal cancer (EC) patients. But which factors may influence the pathological tumor response and long-term survival remains unclear. The purpose of this study was to identify the prognostic biomarkers of locally advanced EC patients receiving neo-CRT.MethodsWe reviewed the data of 72 patients with cT2-4N0-3M0 EC who underwent neo-CRT at our hospital. The patients received intensity-modulated radiation therapy with a total radiation dose of 41.4-60.0 Gy. Most patients received platinum + paclitaxel-based combination regimens every three weeks for 2-4 cycles. The recorded data included age, sex, smoking history, alcohol use, histology, tumor location, clinical TNM stage, tumor length, gross tumor volume (GTV), GTV of primary tumor (GTVp), GTV of lymph nodes (GTVn), radiation dose, and number of chemotherapy cycles. Overall survival (OS), progression-free survival (PFS), and pathological complete response (pCR) were analyzed.ResultsThe 3-year OS and PFS rates of these patients who underwent neo-CRT were 51.14% and 43.28%, respectively. In the univariate analyses, smoking history, clinical stage, GTV, GTVp, and GTVn were significantly associated with OS, whereas alcohol use, GTV, GTVp, and GTVn were significantly associated with PFS. Furthermore, in the multivariate analysis, GTV was an independent prognostic predictor of OS (hazard ratio (HR): 14.14, 95% confidence interval (CI): 3.747-53.33, P < 0.0001) and PFS (HR: 6.090, 95% CI: 2.398-15.47, P < 0.0001). In addition, GTV < 60.50 cm3 compared to > 60.50 cm3 was significantly associated with higher pCR rate (59.3% and 27.8%, respectively, P = 0.038). High dose (> 50 Gy) and increased number of chemotherapy cycles (≥ 3) didn't improve the OS or PFS in patients with GTV > 60.50 cm3.ConclusionGTV was an independent prognostic factor of long-term survival in EC patients, which may be because GTV is associated with histological response to neo-CRT. Additionally, patients with GTV > 60.50 cm3 didn't benefit from increased radiation dose or increased number of chemotherapy cycles.

Project description:BackgroundThe spatial distribution of tumor-infiltrating T cells and its dynamics during chemoradiotherapy combined with PD-1 blockade is little known in esophageal squamous cell carcinoma (ESCC).MethodsWe applied the multiplex immunofluorescence method to identify T cells (CD4+, CD8+ T cells, and their PD-1- or PD-1+ subsets) and myeloid-derived cells (CD11c+ dendritic cells, CD68+ macrophages, and their PD-L1+ subpopulations) in paired tumor biopsies (n = 36) collected at baseline and during combination (40 Gy of radiation) from a phase Ib trial (NCT03671265) of ESCC patients treated with first-line chemoradiotherapy plus anti-PD-1 antibody camrelizumab. We used the FoundationOne CDx assay to evaluate tumor mutational burden (TMB) in baseline tumor biopsies (n = 14). We dynamically assessed the nearest distance and proximity of T-cell subsets to tumor cells under combination and estimated the association between T-cell spatial distribution and combination outcome, myeloid-derived subsets, TMB, and patient baseline characteristics.FindingsWe found that the tumor compartment had lower T-cell subsets than the stromal compartment but maintained a comparable level under combination. Both before and under combination, PD-1- T cells were located closer than PD-1+ T cells to tumor cells; T cells, dendritic cells, and macrophages showed the highest accumulation in the 5-10-μm distance. Higher CD4+ T cells in the tumor compartment and a shorter nearest distance of T-cell subsets at baseline predicted poor OS. Higher baseline CD4+ T cells, dendritic cells, and macrophages were associated with worse OS in less than 10-μm distance to tumor cells, but related with better OS in the farther distance. Higher on-treatment PD-1-positive-expressed CD4+ and CD8+ T cells within the 100-μm distance to tumor cells predicted longer OS. T cells, dendritic cells, and macrophages showed a positive spatial correlation. Both high TMB and smoking history were associated with a closer location of T cells to tumor cells at baseline.ConclusionsWe firstly illustrated the T-cell spatial distribution in ESCC. Combining chemoradiotherapy with PD-1 blockade could improve the antitumor immune microenvironment, which benefits the treatment outcome. Further understanding the precision spatiality of tumor-infiltrating T cells would provide new evidence for the tumor immune microenvironment and for the combination treatment with immunotherapy.

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Pre-treatment tumor-infiltrating T cells influence response to neoadjuvant chemoradiotherapy in esophageal adenocarcinoma.

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