Enhance anti-lung tumor efficacy of chimeric antigen receptor-T cells by ectopic expression of C–C motif chemokine receptor 6

Chimeric antigen receptor-T (CAR-T) cells have limited therapeutic efficacy against solid tumors, partially due to their limited ability to reach and invade into the neoplastic foci. By gene expression profiling interactive analysis, we identified that the C–C motif chemokine ligand (CCL) 20 is highly expressed in lung and other most incidence and/or mortality cancers such as colon, rectum, stomach, and liver cancers. Forced expression of C–C motif chemokine receptor 6 (CCR6), the biunique receptor of CCL20, results in robust trafficking of CAR-T cells toward CCL20-secreting tumor cells. In a lung cancer xenograft mouse model, CCR6-expressing CAR-T cells efficiently migrate to and infiltrate into solid tumors upon infusion, leading to effective tumor clearance and significantly prolonged survival of tumor-bearing mice. In addition, culturing CCR6-CAR-T cells with interleukin (IL)-7 and IL-15 further improved their anti-lung cancer activity. Our findings provide supporting evidence for the clinical development of chemokine receptor-engineered CAR-T cells for solid tumor immunotherapy.