Targeting Tumor-Associated Macrophages to Treat Lymphoma

T cell lymphomas (TCLs) are a highly heterogenous group of lymphoid malignancies originating from mature T cells, representing approximately 12% of all non-Hodgkin lymphomas. TCL remains largely incurable with existing therapies due to its extreme heterogeneity and rapid progression. Novel and more effective treatments for TCL are urgently needed. In this context, we proposed an innovative strategy by inducing tumoricidal activities of tumor-associated macrophages (TAMs) through targeting Ca2+/calmodulin-dependent protein kinase II (CAMK2). Our prior research has underscored the pivotal role of CAMK2 in promoting TCL development, with inhibiting CAMK2 proved to be effective in suppressing TCL progression. Recently, we have unveiled a novel role of CAMK2 kinases in modulating macrophage-mediated immunosurveillance. Upon CAMK2 inhibition, macrophages underwent repolarization and demonstrated enhanced phagocytic activity against TCL cells. We further explore the molecular mechanisms through which CAMK2 regulates antitumoral immunity of TAMs within the tumor microenvironment (TME) and determine the therapeutic potential of CAMK2 inhibition in facilitating the clearance of TCL cells. Our preliminary findings indicate that CAMK2 inhibition reprogrammed human and mouse macrophages toward the M1 phenotype with enhanced phagocytic ability; CAMK2 inhibition induced TFEB nuclear translocation, leading to upregulation of lysosomal genes in macrophages; CAMK2 inhibition accelerated lysosomal biogenesis and acidification in macrophages, facilitating lysosomal-mediated degradation; administration of a small molecule inhibitor targeting CAMK2 suppressed TCL tumor growth while depletion of macrophages reversed its antitumor effect. TFEB is a pivotal regulator of lysosomal biogenesis, and its dephosphorylation prompts nuclear translocation, which subsequently activates lysosomal biogenesis and acidification to augment the phagocytic ability of macrophages. Therefore, we formed the following hypothesis: the inhibition of CAMK2 promotes the phagocytic capacity of macrophages by inducing transcription factor EB (TFEB)-mediated lysosomal activity, leading to enhanced elimination of TCL cells. To scrutinize the hypothesis, the proposed studies comprise three Specific Aims: 1) define the effects of CAMK2 inhibition in reprogramming TAMs toward an anti-tumoral phenotype; 2) dissect the molecular mechanisms underlying CAMK2 inhibition in TAM reprogramming; and 3) determine the efficacy of CAMK2 inhibition in TCL growth with in vivo mouse models. Upon completion of this project, we anticipate unveiling a novel mechanism by which CAMK2 regulates TAM phenotypes and anti- tumor immunity via the CAMK2/TFEB axis. In addition, we expect to reveal the efficacy of targeting the CAMK2/TFEB axis for TCL treatment using preclinical models.