Title: Functional state of CD8+ T cell immunity in adult T-cell leukemia/lymphoma Abstract Adult T-cell leukemia/lymphoma (ATLL) is a fatal disease of malignant CD4+ T cells that develops in human T- lymphotropic virus-1 (HTLV-1) carriers. Recent studies from our group and others further suggest that ATLL diagnosed in the Caribbean region and North America (NA-ATLL) differ from those diagnosed in Japan (J-ATLL) in both clinical presentation and immuno-genetic landscape. More than half of NA-ATLL patients in the U.S. are immigrants of Caribbean descents. Relative to J-ATLL, NA-ATLL cases are diagnosed at a younger age but present a more aggressive disease and face a shorter overall survival. Thus, improved understanding of pathogenesis and novel therapeutic strategies are urgently needed. It is well-known that anti-HTLV-1 immune surveillance plays a key role in preventing ATLL development. Multiple lines of evidence support the notion that ATLL cells achieve immune escape not only by preventing antigen presentation but also by suppressing systemic immune responses in the hosts. Hence, conceptually, therapies that aim to augment anti-ATLL cytotoxic T cell response (CTL) should have therapeutic benefit. Currently, ATLL is often managed with first-line chemotherapy which rarely achieves durable response in NA-ATLL and possibly further damages already weakened CTL activity in the hosts. At the same time, multiple targeted therapies only produced limited clinical efficacy. Most remarkably, two immune-modulating treatments, i.e. the anti-CCR4 mAb mogalizumab and anti-PD-1 mAb Nivolumab, have failed in NA-ATLLs while showing some clinical benefits among Japanese patients, highlighting the need to obtain an in-depth understanding of the host immune function in NA-ATLL. We recently developed a high dimensional spectral flow cytometry panel to achieve in-depth characterization of both transformed and non-transformed T, B, and NK cells in PBMC samples from our Montefiore-Einstein ATLL Biobank. We revealed that ATLL cells exhibited a phenotype associated with robust immunosuppression. We also discovered in these patients a unique population of phenotypically exhausted CD8+ T cells, the proportion of which decreased in a remission patient. In this proposal, we will test the hypothesis that ATLL cells induce a general state of immunosuppression in patients that prevents an effective and durable anti-ATLL effector CD8+ T cell response. Using patient samples from our unique ATLL Biobank and those collected from the Belinostat/Zidovudine/IFN trial conducted by Dr. Ramos (University of Miami), we will define new immune correlates of favorable outcomes in this devastating blood cancer though high dimensional flow cytometry, functional T cell assays, as well as single cell transcriptomic and T cell receptor clonotypic analyses.