S1. Gating strategy of peripheral blood leukocytes and splenocytes was shown to determine immune subpopulations for multi-color flow cytometry assay. S2. Effect of NK depletion antibody (NK1.1) on other immune cells. S3. Effect of CD8 T depletion on other immune cells. S4. NanoString gene expression analysis in tumor microenvironment.
University of Texas MD Anderson Cancer Center
Specialized Program of Research Excellence
Lung Cancer Moon Shot Program
ARTICLE ABSTRACTExpression of the multikinase inhibitor encoded by the tumor suppressor gene TUSC2 (also known as FUS1) is lost or decreased in non–small cell lung carcinoma (NSCLC). TUSC2 delivered systemically by nanovesicles has mediated tumor regression in clinical trials. Because of the role of TUSC2 in regulating immune cells, we assessed TUSC2 efficacy on antitumor immune responses alone and in combination with anti–PD-1 in two Kras-mutant syngeneic mouse lung cancer models. TUSC2 alone significantly reduced tumor growth and prolonged survival compared with anti–PD-1. When combined, this effect was significantly enhanced, and correlated with a pronounced increases in circulating and splenic natural killer (NK) cells and CD8+ T cells, and a decrease in regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and T-cell checkpoint receptors PD-1, CTLA-4, and TIM-3. TUSC2 combined with anti–PD-1 induced tumor infiltrating more than NK and CD8+ T cells and fewer MDSCs and Tregs than each agent alone, both in subcutaneous tumor and in lung metastases. NK-cell depletion abrogated the antitumor effect and Th1-mediated immune response of this combination, indicating that NK cells mediate TUSC2/anti–PD-1 synergy. Release of IL15 and IL18 cytokines and expression of the IL15Rα chain and IL18R1 were associated with NK-cell activation by TUSC2. Immune response–related gene expression in the tumor microenvironment was altered by combination treatment. These data provide a rationale for immunogene therapy combined with immune checkpoint blockade in the treatment of NSCLC. Cancer Immunol Res; 6(2); 163–77. ©2018 AACR.