Characterization of Surgery-Induced Vaccine Dysfunction in a Therapeutic Murine Melanoma Model

Abstract

Surgical resection is the leading treatment of most solid tumours, however surgical stress creates an immunosuppressive environment that promotes metastases. A global decrease in T cell numbers and function post-surgery has been documented. However, the effect on tumour associated antigen (TAA)-specific T cells remains unclear. The objective is therefore to evaluate the impact of surgical stress on TAA-specific adaptive T cell immunity. Melanoma tumour-bearing C57BL/6 mice were vaccinated using AdhDCT, an adenovirus expressing dopochrome totaumerase (DCT), a melanoma TAA, and underwent abdominal nephrectomies to induce surgical stress. Surgical stress decreased the number of splenic cytotoxic T cells (CTLs) and their capacity to produce immunostimulatory cytokines (IFNγ and TNFα), as determined by flow cytometry. A perioperative accumulation in CTL-suppressive MDSCs was observed and demonstrated a direct suppression of CTL IFNγ and TNFα production and secretion. Understanding the mechanisms of perioperative T cell dysfunction will facilitate the development of targeted immunotherapies.