Tumour-infiltrating regulatory T cell density before neoadjuvant chemoradiotherapy for rectal cancer does not predict treatment response.

Melanie J Mccoy,Chidozie C Anyaegbu,Chris Hemmings,Cameron F Platell,Anna K Nowak,Max K Bulsara,Richard A Lake,Nikolajs Zeps,Timothy J Miller,Stephanie J Austin,Tracey F Lee-Pullen

doi:10.18632/oncotarget.15048

Abstract

Neoadjuvant (preoperative) chemoradiotherapy (CRT) decreases the risk of rectal cancer recurrence and reduces tumour volume prior to surgery. However, response to CRT varies considerably between individuals and factors associated with response are poorly understood. Foxp3+ regulatory T cells (Tregs) inhibit anti-tumour immunity and may limit any response to chemotherapy and radiotherapy. We have previously reported that a low density of Tregs in the tumour stroma following neoadjuvant CRT for rectal cancer is associated with improved tumour regression. Here we have examined the association between Treg density in pre-treatment diagnostic biopsy specimens and treatment response, in this same patient cohort. We aimed to determine whether pre-treatment tumour-infiltrating Treg density predicts subsequent response to neoadjuvant CRT. Foxp3+, CD8+ and CD3+ cell densities in biopsy samples from 106 patients were assessed by standard immunohistochemistry (IHC) and evaluated for their association with tumour regression grade and survival. We found no association between the density of any T cell subset pre-treatment and clinical outcome, indicating that tumour-infiltrating Treg density does not predict response to neoadjuvant CRT in rectal cancer. Taken together with the findings of the previous study, these data suggest that in the context of neoadjuvant CRT for rectal cancer, the impact of chemotherapy and/or radiotherapy on anti-tumour immunity may be more important than the state of the pre-existing local immune response.

Highlights

Colorectal cancer is the third most common cancer worldwide, representing almost 10% of all cancer diagnoses [1]
We investigated the relationship between T cell subset density in pre-treatment diagnostic biopsies and response to neoadjuvant CRT in 106 patients with locally advanced rectal cancer
We hypothesised that an existing local anti-tumour immune response dominated by CD8+ cells rather than regulatory T cells (Tregs) would ‘set the scene’ for effective CRT-induced anti-tumour immunity, and better treatment response

Summary

Introduction

Colorectal cancer is the third most common cancer worldwide, representing almost 10% of all cancer diagnoses [1]. Rectal cancer accounts for around one third of colorectal cancer cases. Standard treatment for locally advanced rectal cancer consists of neoadjuvant radiotherapy with concurrent 5-fluorouracil (5-FU)-based chemotherapy (neoadjuvant CRT), followed by surgery. While approximately 20% of patients have a pathologic complete response (defined as no viable tumour cells in the surgical resection specimen), around 60% have a partial or intermediate response, and approximately 20% experience little to no regression [4,5,6]. The benefit of CRT for this latter patient group is less clear and www.impactjournals.com/oncotarget factors associated with response are not well understood. The extent of tumour regression following CRT is associated with improved long-term outcome, even in the context of potentially curative surgery [7,8,9]

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