EBV-Associated Lymphoma Consortium Annual Meeting (Abstract)

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Submission Number: 10

Submission ID: 150870

Submission UUID: db31f8c0-6f4e-42b6-86fd-eda10b07b1f8

Submission URI: /nci/ealv/venue/abstract

Submission Update: /nci/ealv/venue/abstract?token=dgnae_eUGykmczeyX3wj4i824d4DHgYInDPCrAVyf-A

Created: Wed, 09/03/2025 - 21:13

Completed: Wed, 09/03/2025 - 21:13

Changed: Wed, 09/03/2025 - 21:13

Remote IP address: 10.208.24.230

Submitted by: Anonymous

Language: English

Is draft: No

Webform: EBV-Associated Lymphoma Consortium Annual Meeting (Abstracts)

Submitted to: EBV-Associated Lymphoma Consortium Annual Meeting (Abstract)

OMB No.: 0925-0740
Expiration Date: 9/30/2025

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Epstein-Barr virus (EBV) persists in tumors in distinct latency states: latency I (expressing only EBNA1) and latency II-III (expressing immunogenic proteins such as LMP1/2 and/or EBNA2/3, targeted by cytotoxic T cells (CTLs)). We previously reported that latency restriction is regulated by DNA methyltransferase 1 (DNMT1) (Guo et al, Nat Microbiol 2020), and that treatment with decitabine induces latency II/III antigen expression in latency I tumors, sensitizing them to EBV-specific CTLs (Dalton et al, Blood 2020). Beyond latency, DNMT1 also controls cytokine expression by repressing the expression of cytokines (IL1b, IL6, IL4, TNFa) and chemokines (CXCL9, CXCL10). We hypothesized that latency programs generate distinct cytokine milieus, shaping tumor-immune interactions and facilitating immune evasion.
To test this, we compared cytokine expression in latency I and III cell lines and performed spatial molecular imaging in EBV+ HIV-associated lymphomas. DNMT1 was reduced in latency III cells, which produced more IL4, IL6, IL10 and IL21 than latency I cells. To assess heterogeneity in vivo, we performed imaging mass cytometry on 53 EBV+ HIV-associated lymphomas (Burkitt lymphoma, primary effusion lymphoma, diffuse large B cell lymphoma, Hodgkin lymphoma, polymorphic lymphoproliferative disorder and plasmablastic lymphoma). Tumors displayed striking intratumoral heterogeneity, with most cells in latency I but variable subsets in latency IIa, IIb, and III. Consistent with cell line data, latency III tumor cells exhibited elevated IL4, IL6, IL10 and Il21 expression. Neighbourhood analysis revealed that latency I cells were preferentially surrounded by macrophages, CD4+ and CD8+ T cells, whereas latency III cells were enriched for NK cells, dendritic cells and exhausted LAG3+ CD8+ T cells. 
In summary, latency III cells show reduced DNMT1, increased cytokine expression, and distinct immune niches, suggesting that EBV latency programs shape the tumor-immune niche and contribute to immune evasion.