Genetic manipulations to improve intratumoral trafficking of adoptively transferred T cells

Abstract

Abstract T cell–mediated cancer immunotherapies, including anti–PD-1 and CAR-T cells, are becoming standard treatments for many cancer types. One potential strategy to overcome resistance is to enhance the ability of T cells to traffic into tumors. We recently reported results from an innovative, genome-wide screen to identify endogenous T cell genes that enhance intratumoral accumulation using the Sleeping Beauty (SB) transposon system. We successfully identified many promising candidates with this in vivo approach using immunocompetent models of solid tumors. Others have performed similar independent whole-genome and targeted screens in T cells assessing tissue localization using adoptive T cell transfer approaches. To determine how our gene candidates compared with significant candidates identified in these independent screens, we performed a formal rank aggregation to generate a single, integrated ranked list in descending order of selection strength. Aggregated results yielded approximately 1500 T cell gene candidates whose biological functions are enriched in chemotaxis. We hypothesized that these candidates represent novel therapeutic targets to improve T cell migration into solid tumors. Here, we present in vivo validation of two of the most strongly selected candidates, including AP2-associated protein kinase 1 (Aak1) and Small Proline-Rich Protein 1B (SPRR1B). Importantly, in vivo migration of adoptively transferred T cells into tumors was significantly increased when the T cells overexpressed AAK1DN125 or SPRR1B. Our observations strongly support the strength of genomic screens to identify truly novel candidates for further development as immunotherapies to enhance T cell homing to the tumor microenvironment. Supported by Mayo Clinic Graduate School of Biomedical Sciences, K22 (K22CA225786, PI: LM Rogers), and Cancer Immunology and Immunotherapy Program Pilot Award (PI: LM Rogers)