TUSC2 Enhances Sensitivity to Anti-PD1 in Kras Mutant Syngeneic Mouse Lung Cancer Through NK Cells

Abstract

Expression of the tumor suppressor gene TUSC2, a specific multikinase inhibitor, is lost or decreased in several cancer types, including NSCLC. We assessed TUSC2 effects on antitumor activity and immune response alone and in combination with anti-PD1 in two Kras mutant syngeneic mouse lung cancer models. TUSC2 alone significantly reduced tumor growth and survival compared with anti-PD1. When combined, this effect was significantly enhanced. Immune profile analysis showed a pronounced increase of circulating and splenic NK cells, an increase of CD8+ T lymphocytes, and a decrease in the levels of Tregs, MDSCs, and T cell checkpoint receptors PD1, CTLA-4, and TIM-3. TUSC2 alone increased serum levels of IFNɣ, IL15 and IL18. Immunohistochemistry revealed higher tumor infiltration of activated NK and CD8+ T cells by TUSC2 + anti-PD1 than each agent alone. NK depletion abrogated the antitumor effect of this combination, indicating that NK cells are important mediators of TUSC2/anti-PD1 synergy. NanoString analysis showed that this combination significantly altered immune response related gene expression in the tumor microenvironment. These preclinical data provide a rationale for immunogene therapy combined with immune checkpoint inhibitors in the treatment of lung NSCLC.