Chemotherapy accelerates immune-senescence and functional impairments of Vδ2(pos) T cells in elderly patients affected by liver metastatic colorectal cancer

Human (gamma delta) γδ T cells are unconventional innate-like lymphocytes displaying a broad array of anti-tumor activities with promising perspectives in cancer immunotherapy. In this context, Vδ2(pos) T cells represent the preferential target of several immunotherapy protocols against solid tumors. However, the impact of both aging and chemotherapy (CHT) on Vδ2(pos) T cells is still unknown. The present study evaluates with multi-parametric flow cytometry the frequencies, terminal differentiation, senescence and effector-functions of peripheral blood and tumor infiltrating Vδ2(pos) T cells purified from liver metastases (CLM) of patients affected by colorectal cancer (CRC) compared to those of sex- and age-matched healthy donors. The peripheral blood of CLM patients underwent CHT is characterized by decreased amounts of Vδ2(pos) T cells showing a relative increase of terminally-differentiated CD27(neg)/CD45RA(pos) (T(EMRA)) cells. The enrichment of this latter subset is associated with an increased expression of the senescent marker CD57. The acquisition of CD57 on T(EMRA) Vδ2(pos) T cells is also coupled with impairments in cytotoxicity and production of TNF-α and IFN-γ. These features resemble the acquisition of an immune-senescent profile by Vδ2(pos) T cells from CLM patients that received CHT, a phenomenon that is also associated with the loss of the co-stimulatory marker CD28 and with the induced expression of CD16. The group of CLM patients underwent CHT and older than 60 years old showed higher frequencies of CD57(pos) and T(EMRA) Vδ2(pos) T cells. Similar results were found for tumor infiltrating Vδ2(pos) T cell subset purified from CLM specimens of patients treated with CHT. The toxicity of CHT regimens also affects the homeostasis of Vδ2(pos) T cells by inducing higher frequencies of circulating CD57(pos) T(EMRA) subset in CLM underwent CHT and younger than 60 years old. Taken together, our data demonstrate that the enrichment of senescent Vδ2(pos) T cells in CLM patients is not only induced by patients’ aging but also by the toxicity of CHT that further accelerates the accumulation of CD57(pos) T(EMRA) cells highly dysfunctional in their anti-tumor activities. These results are important to both predict the clinical outcome of CLM and to optimize those protocols of cell cancer immunotherapy employing unconventional Vδ2(pos) T cells.