Human immunodeficiency virus (HIV) infection is linked with an increased risk of many types of cancers. With the effect of combination antiretroviral therapy (cART) on reducing acquired immunodeficiency syndrome (AIDS)-defining cancers and the aging of PLWH, non-AIDS-defining cancers (NADCs) have become a major source of mortality in this population, which has been observed across the globe. Among the NADCs, lung cancer is the leading cause of death in PLWH. Non-small- cell lung cancer (NSCLC) is the most common type of lung cancer comprising 85% of all lung cancer cases. HIV infection remains an independent risk factor for NSCLC even after adjusting for potential confounders such as smoking. At the time of initial diagnosis of NSCLC, PLWH are younger than those without HIV infection. Compared to those without HIV infection, HIV-infected patients with NSCLC have a poorer prognosis with median overall survival between 4-6 months. While disparities in receiving cancer treatment have been at least partly attributed to the poor prognosis, HIV-infected patients with NSCLC have poorer outcomes even when they receive stage-appropriate treatment. While chronic inflammation and decreased immune surveillance associated with HIV infection have been suggested as potential mechanisms of lung cancer initiation and metastatic progression in PLWH, whether and to which extent HIV-associated systemic immune dysregulation affects the local immune response in the tumor microenvironment has not been fully evaluated. With the success of cancer immunotherapy such as immune checkpoint inhibitor therapy in the treatment of various cancer types including lung cancer, it has become increasingly important to understand the interactions between the immune system and cancer cells by comprehensively profiling the local immune response in the tumor microenvironment. Elucidation of the tumor immune microenvironment in PLWH suffering from non-small-cell lung cancer (NSCLC) – the most common type of lung cancer – will deepen our understanding of HIV-driven lung cancer tumorigenesis and progression and allow us to devise novel immunotherapeutic approaches designed specifically for PLWH. In this study, we propose to interrogate the expression of inhibitory immune checkpoints and immune cell populations in the tumor microenvironment in HIV-associated and HIV-unassociated NSCLCs, utilizing multiplexed imaging mass cytometry technology (Fluidigm, USA). We will also evaluate the presence of HIV infection in the tumor microenvironment and its impacts on the local immune response using RNAscope in situ hybridization (ACDbio, USA). In the long term, the results of the study have the potential to lay the foundation for development of novel immunotherapeutic strategies in PLWH and NSCLC.