High acidity in solid tumors can inhibit the function of the immune system’s T cells and natural killer cells and compromise adoptive cell therapy and other immunotherapies. In this proof-of-concept study, researchers led by Ludwig’s Scientific Director Chi Van Dang and former graduate student Yao-Yu Gong tested the metabolic engineering of immune effector cells to mitigate the inhibitory effect of tumor acidity. A common feature of advanced tumors, acidity suppresses the activity of a key regulator of metabolism known as mTOR complex 1 (mTORC1) in immune cells. Many studies have found that systemically countering acidity can reverse this effect and support checkpoint blockade immunotherapy. But Chi, Yao-Yu and colleagues reported in Cancer Research Communications in August that in MYC-driven liver cancer, such systemic buffering against acidity enhanced tumor cell mTORC1 activity and thereby dampened the effects of anti-PD-1 checkpoint blockade. To get around this problem, they engineered a natural killer cell line to express a permanently activated ion-exchanging protein, NHE1; SLC9A1, that counters acidity in the immune cells. This resulted in enhanced target engagement and antitumor activity of the cells in mice, demonstrating that the metabolism of immune cells employed for adoptive cell therapies can be engineered to overcome challenges posed by the tumor microenvironment.
Na+/H+-exchanger 1 Enhances Antitumor Activity of Engineered NK-92 Natural Killer Cells
Cancer Research Communications, 2022 August 22