Tumor-Infiltrating Cytotoxic T Cells and Tumor-Associated Macrophages Correlate With the Outcomes of Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer.

Yuqin Yang,Lu Shi,Hong Zhao,Bin Zhao,Qingling Zhang,Xiaohua Gong,Wenjing Tian,Liqian Su,Peiqiu Li

doi:10.3389/fonc.2021.743540

Abstract

BackgroundTumor-infiltrating immune cells (TIICs) play a key role in immunoregulatory networks and are related to tumor development. Emerging evidence shows that these cells are associated with sensitivity to chemotherapy and radiotherapy. However, the predictive role of TIICs in the outcomes of neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC) is unclear.MethodsImaging mass cytometry (IMC) was performed to comprehensively assess the immune status before nCRT in 6 patients with LARC (3 achieved pathological complete response (pCR), 3 did not) with matched clinicopathological parameters. Immunohistochemistry (IHC) for CD8, CD163 and Foxp3 on biopsy samples from 70 patients prior to nCRT and logistic regression analysis were combined to further evaluate its predictive value for treatment responses in an independent validation group.ResultsA trend of increased CD8+ cytotoxic T lymphocytes (CTLs) and decreased CD163+ tumor-associated macrophages (TAMs) and Foxp3+ regulatory T cells (Tregs) in the pCR group was revealed by IMC. In the validation group, CTLs and TAMs were strong predictors of the clinical response to nCRT. High levels of CTLs were positively associated with the pCR ratio (OR=1.042; 95% CI: 1.015~1.070, p=0.002), whereas TAMs were correlated with a poor response (OR=0.969; 95% CI: 0.941~0.998, p=0.036). A high density of TAMs was also associated with an advanced cN stage.ConclusionCTLs in the tumor microenvironment (TME) may improve the response to nCRT, whereas TAMs have the opposite effect. These results suggest that these cells might be potential markers for the clinical outcomes of nCRT and aid in the clinical decision-making of LARC for improved clinical outcomes.

Highlights

Rectal cancer treatment depends on various factors, including clinical stage, pathological grade, and patient age
To comprehensively assess the immune status of locally advanced rectal cancer (LARC) and its correlation to clinical outcomes after Neoadjuvant CRT (nCRT), we developed a 12-antibody panel containing the major Tumor-infiltrating immune cells (TIICs) subsets (including CD4+ T cells, CD8+ cytotoxic T lymphocytes (CTLs), Tregs, NK cells, B cells, monocytes, and tumor-associated macrophages (TAMs)) for the analysis of LARC biopsy samples by imaging mass cytometry (IMC)
After adjusting for demographic factors, including age at diagnosis, sex, pathological type, clinical stage, and chemotherapy regimen, in the multivariate logistic regression analysis, the results showed that a high level of CD8+ CTLs was an independent factor associated with pathological complete response (pCR) (OR=1.042; 95% confidence intervals (CIs): 1.015~1.070, p = 0.002)

Summary

Introduction

Rectal cancer treatment depends on various factors, including clinical stage, pathological grade, and patient age. For patients who are diagnosed with locally advanced rectal cancer (LARC), preoperative 5-fluorouracil-based chemoradiotherapy (CRT), followed by surgery, has been recommended as the standard treatment [1]. Pathological complete response (pCR), defined as no remaining visible tumor cells in the surgical specimen on a histopathologic assessment, has already been proven to be associated with prolonged disease-free survival (DFS) and overall survival (OS) [3]. Numerous studies have been carried out to explore the mechanisms of the clinical response to chemoradiotherapy [5,6,7], but the biomarkers that represent nCRT sensitivity remain poorly understood; further studies are needed to improve the pCR ratio of nCRT. The predictive role of TIICs in the outcomes of neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC) is unclear

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Conclusion