Effects of aging on immunosenescence and checkpoint inhibitor efficacy in a C57BL/6J syngeneic model

Abstract

Abstract Aging is a complex dynamic process that leads to increased susceptibility to various diseases including cancer. Immunosenescence is a state of aging-related gradual deterioration of the immune system in the elderly. T cells are a major part of an adaptive immune system and orchestrate the cellular immune response. However, only limited studies were conducted on how aging, immunosenescence, and cancer therapy affect each other. Our goals in this study were to establish a mouse model that shows immunosenescence and to study how the immunosenescence affects checkpoint inhibitor efficacy in a C57BL/6J syngeneic model. Young (7 weeks of age), mid-aged (54 weeks) and aged (76–78 weeks) female mice were used. The spleen and blood were collected from the naïve mice and analyzed using a flow cytometer. In both samples, we found a decrease in naïve CD4+ and CD8+ T cells in mid-aged and aged mice compared to the young counterparts, which is a sign of immunosenescence. Compared to young mice naïve aged mice showed increased regulatory T cells (Tregs) in the spleen without a significant difference in the blood. When the mice were inoculated with MC38 tumors and treated with isotype control or anti-PD1 antibody for 3 weeks, anti-PD1 treatment was found to significantly slow down tumor growth in all age groups but was the most efficacious in aged mice. Anti-PD1 treatment increased T cell infiltration into the tumor with the greatest effect observed in the mid-aged group. In conclusion, we have established a preclinical mouse model that shows immunosenescence, and immunosenescence is a possible cause of the difference in response to the checkpoint inhibitor in the elderly.