Adoptive cell transfer (ACT)
immunotherapy has remarkable efficacy against some
hematological malignancies. However, its efficacy in solid
tumors is limited by the adverse tumor microenvironment (TME) conditions, most notably that acidity inhibits T and natural killer (NK) cell mTOR complex 1 (
mTORC1) activity and impairs cytotoxicity. In several reported studies, systemic buffering of
tumor acidity enhanced the efficacy of
immune checkpoint inhibitors. Paradoxically, we found in a c-Myc-driven
hepatocellular carcinoma model that systemic buffering increased
tumor mTORC1 activity, negating inhibition of
tumor growth by anti-PD1 treatment. Therefore, in this proof-of-concept study, we tested the metabolic engineering of immune effector cells to mitigate the inhibitory effect of
tumor acidity while avoiding side effects associated with systemic buffering. We first overexpressed an activated RHEB in the human NK cell line NK-92, thereby rescuing
acid-blunted
mTORC1 activity and enhancing cytolytic activity. Then, to directly mitigate the effect of acidity, we ectopically expressed
acid extruder
proteins. Whereas ectopic expression of
carbonic anhydrase IX (CA9) moderately increased
mTORC1 activity, it did not enhance effector function. In contrast, overexpressing a constitutively active
Na+/H+-exchanger 1 (NHE1; SLC9A1) in NK-92 did not elevate
mTORC1 but enhanced degranulation, target engagement, in vitro cytotoxicity, and in vivo antitumor activity. Our findings suggest the feasibility of overcoming the inhibitory effect of the TME by metabolically engineering immune effector cells, which can enhance ACT for better efficacy against solid
tumors.