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Abstract Background: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma that exhibits clinical, pathological, and genetic heterogeneity. While generally thought to be incurable, recently demonstrated clinical activity of both chimeric antigen receptor T (CAR-T) cells and bispecific antibodies suggest that immune-mediated therapies offer substantial benefit in this disease and underscores the value of understanding mechanisms of immune evasion in this disease. Aim: The aim of this project is to uncover distinct cellular networks driving immune evasion in MCL across disease sites. Methods: We analyzed 10 archival samples collected from 8 clinically annotated patients with untreated MCL, including mononuclear cells from peripheral blood (PB), lymph nodes (LN) and bone marrow (BM). After generating single-cell suspensions from tumors, we performed Cellular Indexing of Transcriptomes and Epitopes sequencing (CITE-seq) and identified malignant B cells based on the co-expression of cyclin D1 (CCND1) and B cell markers (MS4A1, CD79A, CD79B). B and T cells were then subclustered using a reference mapping geneset. Molecular signatures database was utilized to perform geneset enrichment analysis (GSEA). Results: Our study first confirms the heterogeneity of mantle cell lymphoma across compartments (i. e PB, LN, BM), showing 5 different clusters of malignant cells, with different abundance in cell proportion among patients. We found that malignant B cells expressed different levels of CCND1 expression across tissue compartments. Furthermore, we identified a specific cluster of malignant cells, enriched in the PB, marked by decreased expression of the costimulatory receptor CD40 and higher levels of B-cell receptor signaling. This may explain the rapid response of circulating MCL cells to Bruton Tyrosine Kinase (BTK) inhibition. Interestingly, the higher expression of CD40 on LN-resident MCL cells suggests that MCL cells may co-opt LN-resident T-cells to support their growth, as has been previously described. Consistent with this, T-cells from LN were phenotypically exhausted, suggesting that MCL cells within the LN leverage local interactions with T-cells to promote survival while avoiding T-cell-driven cytotoxicity. Finally, we also found that high level of Ki67 correlates with myeloid-cell abundance in the TME suggesting that monocytes may support tumor cell proliferation. Conclusion: These results provide a deeper understanding of tissue-specific heterogeneity in MCL, including distinct tumor-immune interactions at different tissue sites. In ongoing analyses, we will correlate these findings with patient outcomes and response to BTK inhibition and are currently analyzing samples from patients with relapsed disease to identify microenvironmental features associated with disease progression. Citation Format: Amira Marouf, Jahan Rahman, Ashlee Joseph, Irem Isgor, Ya-Hui Lin, Ronan Chaligne, Shenon Sethi, Ahmet Dogan, Gilles Salles, Anita Kumar, Santosha A Vardhana. Identifying tissue-specific drivers of immune evasion in Mantle Cell Lymphoma at single cell level abstract. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5 (3Suppl): Abstract nr PO-025.
Marouf et al. (Wed,) studied this question.