Tumors, especially non-Hodgkin lymphomas (NHL), are particularly common in immunocompromised patients (ID: transplant recipients or HIV+ individuals). NHL in ID patients is characterized by a frequent association with EBV infection and/ or cerebral localization, both of which can impact the anti-tumor immune response. Cancer in HIV+ patients can benefit from treatment with immune checkpoint inhibitors (ICPi). In these different situations, the development, depth, and characterization of the immune response directed against tumor antigens or viral antigens are of paramount importance in defining markers of treatment response and/ or resistance and therapeutic targets.In the first part of this work, we studied the immunogenomics of 68 B-cell lymphoproliferations: 51 ID patients (34 transplant recipients, 17 HIV+) and 17 immunocompetent individuals (IC), characterizing tumor mutational burden (TMB), mutational profile, the number of neoepitopes, the tumor microenvironment (TME), and peripheral-specific T-cell responses, based on tumor whole-exome and RNA sequencing data and peripheral blood mononuclear cells (PBMCs). Neoepitope prediction from RNA sequencing data was performed using a bioinformatics pipeline developed within our institution.Seventy-two percent of patients had diffuse large-B-cell lymphoma, 25% had cerebral localization, and 40% of tumors were EBV-positive. TMB (2.2 vs. 3.4/Mb, p=0.004) and the number of neoepitopes (40 vs. 200, p=0.00019) were lower in EBV-positive NHL compared to EBV-negative NHL, regardless of immune status. The tumor mutational profile differed based on both EBV status and immune status. HNRNPF and STAT3 mutations were exclusively observed in EBV-positive NHL and ID, respectively. Specific T-cell responses to tumor neoepitopes were detected in all cases of EBV-negative lymphomas but only in half of the cases of EBV-positive lymphomas (p=0.08). Responses were notably directed against neoepitopes derived from IgH and restricted by class II MHC. TME analysis showed increased CD8+ T-cell infiltrate in EBV-positive NHL and a more tolerogenic profile composed of Tregs, M2 macrophages, and increased expression of genes involved in negative immunoregulation.In the second part of this work, we studied the impact of anti-PD-1 antibodies on HIV reservoirs and antiviral immune responses in people living with HIV (PLWH) and treated for cancer, to investigate the possibility of a “shock and kill” strategy with these treatments. We evaluated, at various time points in peripheral blood, the number of CD4+ lymphocytes, plasma HIV RNA, HIV DNA, viral loads of EBV, CMV, HBV, HCV, and HHV-8, activation markers and the expression of different ICP on lymphocytes, and anti-viral specific T cells.Thirty-two patients were included, with a median follow-up of 5 months. HIV DNA tended to decrease before cycle 2 (p = 0.049). Notably, six patients showed a ≥0.5 log10 decrease in HIV DNA at least once, and the HIV DNA of one of these patients became undetectable for a prolonged period of 10 months. However, no significant increase in specific immunity against HIV was observed during treatment. Conversely, an early increase in CTLA-4 expression on the surface of CD4+ T cells (p = 0.004), and TIM-3 and CTLA-4 on the surface of CD8+ T cells, was more pronounced in patients without a reduction in HIV DNA compared to others (p ≤ 0.03).In conclusion, our results suggest the presence of an immune response directed against tumor antigens, especially against neoepitopes derived from IgH and presented by class II MHC, in ID NHL. In PLWH, there is also a specific anti-HIV T-cell response but without the possibility of significant amplification by ICPi in monotherapy. Moreover, we demonstrated a strong involvement of EBV in the immunogenomics of ID NHL (from mutational profile to TME), and a potential mechanism of resistance to ICPi by overexpression of other, which can both allow the development of targeted treatments.