updates

+CD70 is a costimulatory molecule expressed on some activated lymphocytes and has a role in T-cell-mediated immune responses. CD70 aberrations are relatively common in DLBCL and appear more frequent in certain DLBCL patient populations. For instance, in a Chinese DLBCL cohort, 24% of cases exhibited CD70 genetic changes, compared to 10.8% in a Swedish cohort.¹ CD70 mutations are associated with the BN2 genetic subtype of DLBCL.² The mutation pattern in CD70 is consistent with the preferential accumulation of *inactivating mutations*. Loss of CD70 protein expression has been described.¹ Genetic perturbation limits the development of an effective CD8+ T-cell immune response in Bcl6-driven DLBCL. [@nieDualRoleCD702022b]

+In mouse models, CD70 loss promoted lymphomagenesis, consistent with its role as a tumor suppressor gene in B-cell lymphomas.[@mandatoAbstractA38Cd702022]

+@article{mandatoAbstractA38Cd702022,

+ title = {Abstract {{A38}}: {{Cd70}} Genetic Perturbation Limits the Development of an Effective {{CD8}}+ {{T-cell}} Immune Response to {{Bcl6-driven}} Diffuse Large {{B-cell}} Lymphoma},

+ shorttitle = {Abstract {{A38}}},

+ author = {Mandato, Elisa and Calabretta, Eleonora and Bai, Gali and Song, Li and Sun, Yanbo and Shanmugam, Vignesh and Paczkowska, Julia and Choi, Il-Kyu and Redd, Robert and Tang, Ming and Lawton, Lee N and Neuberg, Donna and Rodig, Scott and Michor, Franziska and Zhang, Baochun and Shipp, Margaret A},

+ date = {2022-09-06},

+ journaltitle = {Blood Cancer Discovery},

+ shortjournal = {Blood Cancer Discovery},

+ volume = {3},

+ pages = {A38},

+ issn = {2643-3230},

+ doi = {10.1158/2643-3249.LYMPHOMA22-A38},

+ url = {https://doi.org/10.1158/2643-3249.LYMPHOMA22-A38},

+ urldate = {2024-06-09},

+ abstract = {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 Bcl6tg/+ mice to obtain Cd70−/−; Bcl6tg/+ animals. In our aging cohorts, Cd70−/−; Bcl6tg/+ mice developed significantly increased numbers of histopathologically confirmed DLBCLs at earlier timepoints, compared to Bcl6tg/+ animals. Both the Cd70−/−; Bcl6tg/+ and Bcl6tg/+ 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−/−; Bcl6tg/+ versus Bcl6tg/+ mice, we harvested spleens from asymptomatic animals in each cohort at 6, 14 and 18 months (mo). Cd70−/−; Bcl6tg/+ mice exhibited significantly earlier onset splenomegaly than Bcl6tg/+ 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−/−; Bcl6tg/+ animals. Cd70−/−; Bcl6tg/+ and Bcl6tg/+ 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−/−; Bcl6tg/+ animals expressed significantly higher levels of exhaustion markers than those in Bcl6tg/+ mice. Consistent with this finding, there was a more limited expansion and a subsequent contraction of these splenic CD8+ CTLs in Cd70−/−; Bcl6tg/+ mice, in comparison to Bcl6tg/+ animals. Taken together, these findings suggest that initial anti-tumor immune responses are less effective in Cd70−/−; Bcl6tg/+ mice than in Bcl6tg/+ 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.},

+ issue = {5\_Supplement},

+ file = {/Users/rmorin/Zotero/storage/5BDLJZLQ/Abstract-A38-Cd70-genetic-perturbation-limits-the.html}

+}

+

+@article{nieDualRoleCD702022b,

+ title = {The Dual Role of {{CD70}} in {{B-cell}} Lymphomagenesis},

+ author = {Nie, Man and Ren, Weicheng and Ye, Xiaofei and Berglund, Mattias and Wang, Xianhuo and Fjordén, Karin and Du, Likun and Giannoula, Yvonne and Lei, Dexin and Su, Wenjia and Li, Wei and Liu, Dongbing and Linderoth, Johan and Jiang, Chengyi and Bao, Huijing and Jiang, Wenqi and Huang, Huiqiang and Hou, Yong and Zhu, Shida and Enblad, Gunilla and Jerkeman, Mats and Wu, Kui and Zhang, Huilai and Amini, Rose-Marie and Li, Zhi-Ming and Pan-Hammarström, Qiang},

+ date = {2022-12},

+ journaltitle = {Clinical and Translational Medicine},

+ shortjournal = {Clin Transl Med},

+ volume = {12},

+ number = {12},

+ eprint = {36471481},

+ eprinttype = {pmid},

+ pages = {e1118},

+ issn = {2001-1326},

+ doi = {10.1002/ctm2.1118},

+ abstract = {BACKGROUND: CD70 is a costimulatory molecule that is transiently expressed on a small set of activated lymphocytes and is involved in T-cell-mediated immunity. However, the role of CD70 in B-cell malignancies remains controversial. METHODS: We investigated the clinical relevance of CD70 genetic alterations and its protein expression in two diffuse large B-cell lymphoma (DLBCL) cohorts with different ethnic backgrounds. We also performed transcriptomic analysis to explore the role of CD70 alterations in tumour microenvironment. We further tested the blockade of CD70 in combination with PD-L1 inhibitor in a murine lymphoma model. RESULTS: We showed that CD70 genetic aberrations occurred more frequently in the Chinese DLBCL cohort (56/233, 24.0\%) than in the Swedish cohort (9/84, 10.8\%), especially in those with concomitant hepatitis B virus (HBV) infection. The CD70 genetic changes in DLBCL resulted in a reduction/loss of protein expression and/or CD27 binding, which might impair T cell priming and were independently associated with poor overall survival. Paradoxically, we observed that over-expression of CD70 protein was also associated with a poor treatment response, as well as an advanced disease stage and EBV infection. More exhausted CD8+ T cells were furthermore identified in CD70 high-expression DLBCLs. Finally, in a murine lymphoma model, we demonstrated that blocking the CD70/CD27 and/or PD1/PD-L1 interactions could reduce CD70+ lymphoma growth in vivo, by directly impairing the tumour cell proliferation and rescuing the exhausted T cells. CONCLUSIONS: Our findings suggest that CD70 can play a role in either tumour suppression or oncogenesis in DLBCL, likely via distinct immune evasion mechanisms, that is, impairing T cell priming or inducing T cell exhaustion. Characterisation of specific dysfunction of CD70 in DLBCL may thus provide opportunities for the development of novel targeted immuno-therapeutic strategies.},

+ langid = {english},

+ pmcid = {PMC9722974},

+ keywords = {Animals,B-Lymphocytes,CD27 Ligand,CD70,CD8-Positive T-Lymphocytes,diffuse large B-cell lymphoma,Epstein-Barr Virus Infections,genetic aberration,HBV infection,Humans,immune evasion,Lymphoma Large B-Cell Diffuse,Mice,Tumor Microenvironment},

+ file = {/Users/rmorin/Zotero/storage/747DYURZ/Nie et al. - 2022 - The dual role of CD70 in B-cell lymphomagenesis.pdf}

+}