Lung cancer is the leading cause of cancer mortality worldwide (1). More than 80% of lung cancers consist of non-small cell lung cancer (NSCLC) and activating mutations within EGFR occur in ~50% of Asian patients and ~20% of Western patients with NSCLC (1). Contrary to prevailing notions, EGFR mutations in NSCLC occur in both males and females and in both nonsmokers and nonsmokers (1). Thus, targeting EGFR against development of NSCLC will have significant impact to control this disease. In order to maximize efficacy of preventive approaches in NSCLC, the initial focus will be directed toward patients with premalignant lesions or those with previously treated lung cancer. Two promising therapeutic approaches in preventing development of NSCLC are with interventions designed to attenuate tumor development (chemoprevention) or modulate immune recognition of tumor (immunoprevention). This multi-PI proposal will test innovative chemoimmunopreventive strategies for lung cancer, combining the expertise from Dr. You's and Dr. Wang's research groups in chemoprevention and cancer immunotherapy, respectively. Prior work in Dr. You's laboratory has established retinoid X receptor (RXR) agonists (bexarotene and an analog UAB30) as potent chemopreventive agents in mouse models of lung cancer (2, Table 1). Dr. You's group was also the first to demonstrate remarkable efficacy of an immunopreventive multi-peptide EGFR vaccine against EGFR-driven lung tumorigenesis (3). Dr. Wang's prior work has established a novel immune checkpoint protein VISTA as a critical regulator of anti-tumor immunity (4-9), an important contribution given that blockade of immune checkpoint receptors has been identified as a major breakthrough in cancer treatment (10). Dr. Wang's group has shown that VISTA-blocking mAb enhances T cell-mediated tumor rejection in multiple preclinical mouse models (4-9). Given the established efficacy of these aforementioned approaches in controlling tumor growth, we hypothesize that combinatorial approaches of chemoimmunoprevention will enhance anti-tumor immunity within the tumor microenvironment (TME), which will inhibit lung tumor progression and recurrence. Three specific aims are proposed to test this hypothesis. Aim 1 will investigate the immune regulatory role of RXR agonists in preventing establishment of a tumor microenvironment that suppresses T cell activation against developing lung cancer. Aim 2 will determine the preventive efficacy of combined treatment of RXR agonists and a MHCII-restricted EGFR multi-peptide vaccine on EGFR-driven lung tumor progression. Aim 3 will test the hypothesis that blocking immune checkpoint proteins VISTA and PD-L1 will synergize with RXR agonists/EGFR vaccine to prevent acquired resistance and tumor recurrence. This proposal is highly significant because of the potential of chemoimmunoprevention to become a breakthrough preventive approach for lung cancer.