Low stromal Foxp3+ regulatory T-cell density is associated with complete response to neoadjuvant chemoradiotherapy in rectal cancer

Abstract

Background:Foxp3+ regulatory T cells (Tregs) play a vital role in preventing autoimmunity, but also suppress antitumour immune responses. Tumour infiltration by Tregs has strong prognostic significance in colorectal cancer, and accumulating evidence suggests that chemotherapy and radiotherapy efficacy has an immune-mediated component. Whether Tregs play an inhibitory role in chemoradiotherapy (CRT) response in rectal cancer remains unknown.Methods:Foxp3+, CD3+, CD4+, CD8+ and IL-17+ cell density in post-CRT surgical samples from 128 patients with rectal cancer was assessed by immunohistochemistry. The relationship between T-cell subset densities and clinical outcome (tumour regression and survival) was evaluated.Results:Stromal Foxp3+ cell density was strongly associated with tumour regression grade (P=0.0006). A low stromal Foxp3+ cell density was observed in 84% of patients who had a pathologic complete response (pCR) compared with 41% of patients who did not (OR: 7.56, P=0.0005; OR: 5.27, P=0.006 after adjustment for presurgery clinical factors). Low stromal Foxp3+ cell density was also associated with improved recurrence-free survival (HR: 0.46, P=0.03), although not independent of tumour regression grade.Conclusions:Regulatory T cells in the tumour microenvironment may inhibit response to neoadjuvant CRT and may represent a therapeutic target in rectal cancer.

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

“…Similar results were found in a univariate analyses [78–80]. McCoy et al found a low stromal T reg count to be associated with tumor regression, but not with overall survival [82]. To the best of our knowledge, this question has not been comprehensively addressed using semi-quantitative H&E based scoring such as the Klintrup-Mäkinen grade.…”

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse

“…Accordingly, T reg overexpression has been considered detrimental for cancer patient survival, even though, we and others have described that a high T reg primary tumor infiltration score represents a good prognostic factor for colorectal cancer patients. 18,26,52,59 Even though our results have a major limitation in the low number of patients enrolled, we showed for the first time, to the best of our knowledge, a potential inverse correlation between PD-1 C TIL score and prostate patient bDFS. PD-1 is an inhibitory immune checkpoint receptor which is expressed on activated antigen specific CTLs during the efferent phase of the immune response.…”

“…The results of several studies have already shown that occurrence of autoimmunity, a systemic chronic inflammation profile, as well as the level of tumor infiltration by different lymphocyte subsets and macrophages, may indeed predict the outcome of patients with different disease including non small cell lung cancer (NSCLC), colorectal carcinoma (CRC), breast cancer, melanoma and other malignant diseases. [16][17][18][19][20][21][22][23][24][25] In particular, the results of previous studies by our group showed that primary tumor infiltration by immune-regulatory T cells (CD25 , namely T cm ) are associated to a prolonged PFS and OS in patients with metastatic colorectal carcinoma undergone frontline chemotherapy. [26][27][28] On these bases, we investigated whether infiltration of the primary tumor by different lymphocyte subsets may predict the outcome of PC patients.…”

Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer

“…McCoy et al evaluated the relationship of subset densities of TILs in post-nCRT surgical samples from 128 rectal cancer patients. Low stromal Foxp3+ cell density was significantly associated with pCR (adjusted odds ratio = 5.27, p = 0.006) and improved recurrence-free survival (hazard ratio = 0.46, p = 0.03) [79]. …”