Project summary People with HIV (PWH) are living longer and healthier lives thanks to combination antiretroviral therapy (cART). However, they are experiencing an increased risk for non-AIDS–defining cancers. About 10% of deaths in PWH in the U.S. are now due to non–AIDS-defining cancers, including hepatocellular carcinoma (HCC) and Non-small Cell Lung Cancer (NSCLC). Immunotherapy using Immune Checkpoint Inhibitors (ICIs) has improved outcomes of HCC and NSCLC in the general population, but outcomes in PWH are less clear. The tumor immune microenvironment (TIME) in HCC and NSCLC is characterized by high levels of tumor-associated plasmacytoid dendritic cells (TApDCs), which contribute to immunosuppression and promote tumor growth. In PWH, even in those treated with cART, circulating pDCs induce the killing of T cells, reducing their infiltration into tumors and immunotherapeutic potential. Our long-term goals are to study functions of TApDCs in TIME of HIV-associated HCC and NSCLC, and to develop novel therapeutics to treat such cancers in PWH. This project is based on our extensive experience and preliminary results, including the following. i) pDC depletion in HIV-infected humanized mice rescued anti-HIV CD8+ T cells to control HIV persistence. ii) pDC depletion resolved inflammation, reversed immune exhaustion and rescued activity of anti-tumor CD8+ T cells. iii) In humanized NSG mice with human immune cells and liver tumor (HCC-HIT mice), TApDC enhanced human tumor growth, associated with accumulation of TA-Treg and exhausted CD8 T cells. iv) Depletion of human TApDC in HCC-HIT mice reduced HCC growth, rescued stem-like CD8 T cells in number and functions, and decreased TA-Tregs. We hypothesize that the effects of TApDC in TIME are exacerbated by HIV (even during cART) and contribute to more severe immune suppression or resistance to PD1 ICI immunotherapy. Depletion of TApDC will reprogram TIME to reduce TA-Treg and rescue anti-tumor T cells that respond to PD-1 ICI therapy. We have established two humanized mouse models that support HIV infection and human liver cancer (HCC-HIT mice, Drs. Geng and Su) or human lung cancer (NSCLC-HIT mice, Dr. Heredia). We propose to 1) study how HIV infection affects tumor growth and TApDC/TIME in HCC and NSCLC and 2) to investigate how TApDC interact with ICIs to control tumors in HCC-/NSCLC-HIT mice. We will achieve the following milestones in the two years: (i) characterization of HCC/NSCLC TIME including HIV-enhanced TApDC to suppress T cells and exacerbate tumor growth; and (ii) preclinical testing of TApDC depletion alone and in combination with PD1 ICI in HCC (HCC-HIT mice) and NSCLC (NSCLC-HIT mice) with HIV infection. This will set the foundation to establish a strong program in studying HIV-associated cancers in the UMGCCC. Findings from the project will have a great impact on our understanding of TApDC in HCC/NSCLC TIME, HIV-induced mechanisms of cancer promotion, and on discovering a novel thera...