Examining Post-Operative Antigen Specific CD8⁺ T Cell Dysfunction

Abstract

Surgery remains the most effective approach to cure patients with solid malignancies. However, surgical trauma results in significant cellular immunosuppression. CD8⁺ T cell dysfunction post-operatively has been characterized, however the effects of surgery on antigen specific CD8⁺ T cell suppression has not been fully explored. Here, we established that surgery-induces antigen specific CD8⁺ T cell dysfunction, including impaired pro-inflammatory cytokine secretion and cytotoxicity in patients and mice. We developed a model to investigate surgical stress and cancer recurrence in C57Bl/6 mice, based on transfer of CD8⁺ OT-I T cells, reactive to ovalbumin (OVA), followed by challenge with B16-OVA melanoma cells. This model demonstrates 100% protection against cancer in control animals but 0% protection following surgery. Using a COVID-19 immunological tool kit to characterize post-operative function, we observed a significant suppression in T cells from vaccinated cancer patients. The OT-I model was used to evaluate the mechanisms of post-operative T cell dysfunction. We first established that a population of surgery induce Myeloid Derived Suppressor Cells (sxMDSCs) also known as GR-1⁺ cells in mice which expand after surgery in mice and cancer patients on post-operative day 1 (POD1), are suppressive of CD8⁺ T cells. We then performed single cell RNA sequencing, which identified the intracellular checkpoint CISH (Cytokine-inducible SH2-containing protein) as upregulated in antigen-stimulated human and murine CD8⁺ T cells following surgical stress. Overall, this work highlights antigen specific CD8⁺ T dysfunction post-operatively and uncovers a possible mechanism of dysfunction characterized by the expression of an intracellular checkpoint CISH.