The following is a summary of “Targeting of the CD161 Inhibitory Receptor Enhances T cell-mediated Immunity Against Hematological Malignancies,” published in the December 2023 issue of Hematology by Calderon et al.

The CD161 inhibitory receptor, abundantly expressed by tumor-infiltrating T-cells across various human solid tumor types, encounters its ligand CLEC2D present in tumor and myeloid cells. This study aimed to investigate the role of the CD161 receptor in hematological malignancies. Analyzing CLEC2D expression via the Cancer Cell Line Encyclopedia (CCLE) revealed heightened CLEC2D mRNA levels in diverse hematological malignancies, encompassing B-cell and T-cell lymphomas, lymphocytic, and myelogenous leukemias. Employing flow cytometry, the study group detected CLEC2D protein in a spectrum of hematological malignancy cell lines. Consequently, using yeast display, the researchers generated a suite of fully human CD161 monoclonal antibodies (mAbs) with a high affinity that obstructed CLEC2D binding. 

These mAbs, specific to CD161 and displaying similar affinities for human and non-human primate CD161, hold promise for clinical translation. A high-affinity CD161 mAb augmented pivotal facets of T-cell function—such as cytotoxicity, cytokine production, and proliferation—against ALL, DLBCL, and Burkitt lymphoma-derived B-cell lines from patient sources. This CD161 mAb significantly bolstered T-cell-mediated immunity in humanized mouse models, leading to a notable survival advantage. Single-cell RNA sequencing (scRNA-seq) data demonstrated that CD161 mAb treatment amplified the expression of cytotoxicity genes in CD4 T-cells and activated a tissue-residency program in both CD4 and CD8 T-cells, associated with favorable survival outcomes across multiple human cancer types. These entirely human monoclonal antibodies emerge as prospective immunotherapeutic agents for combatting hematological malignancies.

Source: sciencedirect.com/science/article/abs/pii/S0006497123147367