Do regulatory T cells inhibit the response of rectal carcinomas to neoadjuvant chemoradiotherapy? — ASN Events
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Do regulatory T cells inhibit the response of rectal carcinomas to neoadjuvant chemoradiotherapy? (#12)

Melanie J McCoy 1 2 , Tim J Miller 1 , Chris Hemmings 3 4 , Anna K Nowak 2 , Richard A Lake 2 , Nikolajs Zeps 1 4 , Cameron F Platell 1 4
  1. St John of God Subiaco Hospital, Subiaco, WA, Australia
  2. School of Medicine, University of Western Australia, Perth, Western Australia, Australia
  3. St John of God Pathology, Perth, Western Australia, Australia
  4. School of Surgery, University of Western Australia, Perth, Western Australia, Australia

Background

Chemoradiotherapy prior to surgery (neoadjuvant CRT) is recommended for locally advanced rectal cancer.  Approximately 20% of patients achieve a complete response to CRT (no residual tumour at resection) and have a significantly improved prognosis.  However, around 40% of patients have little or no tumour regression and factors that distinguish responders from non-responders are poorly understood.

Tumour-infiltration by regulatory T cells (Treg), a subset of CD4+ T cells that negatively regulate immune responses, has strong prognostic significance in many cancers, including colorectal cancer.  Pre-clinical studies have shown chemotherapy and radiotherapy can enhance anti-tumour immunity, in part through depletion of Treg, and that chemotherapy efficacy has an immune-mediated component.  This study aimed to determine whether Treg density in the local tumour environment at resection is associated with response to neo-adjuvant CRT in rectal cancer.

Methods

Lymphocytes expressing the transcription factor Foxp3 (constitutively expressed by Treg) were identified in representative areas of residual tumour, stroma and normal epithelium from 130 consecutive cases of neoadjuvantly-treated rectal cancer using standard immunohistochemistry methods. Response to CRT was assessed using the Dworak grading system.

Results

A lower density of Treg in the tumour stroma at resection was significantly associated with better response to CRT (p = 0.019).  The median density of stromal Treg was significantly lower in good/complete responders versus poor responders (19 versus 39 cells / mm2; p = 0.005) and in complete responders versus all other groups (16 versus 33 cells / mm2; p = 0.016).

Conclusions

These data suggest that Treg may inhibit the response of rectal carcinomas to CRT and/or Treg depletion may contribute to treatment efficacy.  If confirmed in further studies, Treg-depleting therapies could be considered in combination with CRT with the aim of improving treatment response rates.