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Multiple immunomodulatory pathways shape the development of anti-tumor immune responses to lymphoid malignancies. We previously defined the recurrent genetic alterations in diffuse large B-cell lymphoma (DLBCL) and identified associated substructure and additional potential genetic bases for immune escape. CD70 was the most commonly perturbed immune response pathway component in our cohort of primary DLBCLs; alterations included inactivating mutations and copy loss. CD70 co-stimulation of CD27+ T cells induces antigen-dependent T-cell expansion and immune surveillance of normal and malignant B cells. Given the frequent co-association of CD70 alterations and BCL6 translocations in our DLBCL patient series, we assessed the consequences of Cd70 deficiency on Bcl6-driven lymphomagenesis in a murine model. We crossed previously generated Cd70 −/- and Bcl6 tg/+ mice to obtain Cd70 −/−; Bcl6 tg/+ animals. In our aging cohorts, Cd70− / −; Bcl6tg/+ mice developed significantly increased numbers of histopathologically confirmed DLBCLs at earlier timepoints, compared to Bcl6 tg/+ animals. Both the Cd70 −/−; Bcl6 tg/+ and Bcl6 tg/+ mice that were euthanized for symptoms exhibited massive splenomegaly and lymphomatous splenic infiltration. None of the wild-type (WT) and Cd70 −/- animals developed lymphoma. To characterize potential differences in anti-tumor responses in Cd70 −/−; Bcl6 tg/+ versus Bcl6 tg/+ mice, we harvested spleens from asymptomatic animals in each cohort at 6, 14 and 18 months (mo). Cd70 −/−; Bcl6 tg/+ mice exhibited significantly earlier onset splenomegaly than Bcl6 tg/+ animals (both in comparison with WT mice). We performed single cell RNA sequencing of splenic cell suspensions from each murine cohort at the above-mentioned predetermined timepoints (6, 14 and 18 mo) and describe genotype-related changes in splenic CD8+ T-cell infiltration in this abstract. Our study revealed an age-related decline in the percentages of naive CD8+ T cells in all genotypes, with more striking and earlier changes in Cd70 −/−; Bcl6 tg/+ animals. Cd70 −/−; Bcl6 tg/+ and Bcl6 tg/+ mice exhibited a selective and significant expansion of CD8+ cytotoxic T cells (CTLs), which expressed Gzmb and Prf1 and the exhaustion markers, Pdcd1, Lag3, Tigit, Tox and Tim3, and exhibited clonal expansion. At 6 mo, prior to splenic enlargement and the development of symptoms, CD8+ CTLs in Cd70 −/−; Bcl6 tg/+ animals expressed significantly higher levels of exhaustion markers than those in Bcl6 tg/+ mice. Consistent with this finding, there was a more limited expansion and a subsequent contraction of these splenic CD8+ CTLs in Cd70 −/−; Bcl6 tg/+ mice, in comparison to Bcl6 tg/+ animals. Taken together, these findings suggest that initial anti-tumor immune responses are less effective in Cd70 −/−; Bcl6 tg/+ mice than in Bcl6 tg/+ animals and highlight the likely importance of CD70/CD27 co-stimulation in CD8+ T-cell response to Bcl6-driven DLBCL. Citation Format: Elisa Mandato, Eleonora Calabretta, Gali Bai, Li Song, Yanbo Sun, Vignesh Shanmugam, Julia Paczkowska, Il-Kyu Choi, Robert Redd, Ming Tang, Lee N Lawton, Donna Neuberg, Scott Rodig, Franziska Michor, Baochun Zhang, Margaret A Shipp. Cd70 genetic perturbation limits the development of an effective CD8+ T-cell immune response to Bcl6-driven diffuse large B-cell lymphoma [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A38.