Mantle cell lymphoma (MCL), accounting for 6-8% of all non-Hodgkin lymphomas (NHLs), is an aggressive and difficult-to-treat B-cell malignancy. MCL patients have a dismal prognosis with a median overall survival of only 3-5 years owing to frequent relapse and resistance to contemporary chemotherapy. Despite recent treatment advances with the FDA-approved drug ibrutinib, which targets the B-cell receptor (BCR) signaling molecule Bruton?s tyrosine kinase (BTK), one-third of MCL patients are ibrutinib-resistant, and even ibrutinib-sensitive patients eventually acquire resistance to the drug. Patients who are insensitive or progress during ibrutinib treatment have very poor outcomes. Thus, more effective post-ibrutinib treatments are urgently needed. Abnormal BCR signaling plays a key oncogenic signal in MCL, but the underlying mechanism is not known. Using an integrated functional genomics approach combining a genome-wide CRISPR-Cas9 screen and gene expression profiling, our group has uncovered CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule-1) as a potential contributor to BCR hyperactivity in MCL. CEACAM1 is a type 1 transmembrane protein expressed as different isoforms due to alternative splicing in epithelial cells and activated leukocytes. In contrast to the short isoform, the CEACAM1 long isoform possesses a cytoplasmic tail that contains the immunoreceptor tyrosine-based inhibitory motif (ITIM) known to negatively regulate the antigen receptor signaling in T cells. We found that CEACAM1 is overexpressed specifically in MCL, as compared to nave B cells or other B-cell malignancies. Consistent with our CRISPR screen results, depletion of CEACAM1 is toxic in multiple MCL cell lines, but not in non-MCL lymphoma cells. CEACAM1 depletion also markedly reduced proximal BCR signaling (e.g., SYK phosphorylation) and BCR-mediated Ca2+ signaling. More importantly, using T cells that express the CEACAM1-specific chimeric antigen receptor (CAR), we showed that these CAR T cells could effectively eliminate MCL tumors while sparing non-MCL lymphoma in vitro. On the basis of these findings, we hypothesize that CEACAM1 is essential for the oncogenic BCR signaling in MCL and thus a valid therapeutic target for this malignancy. We will test the hypothesis through accomplishing the following specific aims: 1) Determine the mechanisms underlying CEACAM1-regulated BCR signaling; 2) Characterize the MCL-specific expression of CEACAM1; 3) Develop a CAR T-cell strategy to treat MCL in vivo using pre-clinical patient-derived xenograft (PDX) models. Findings from this proposal will improve our limited knowledge of the role of CEACAM1 in MCL pathogenesis. We anticipate that successful completion of the project will provide relevant pre-clinical data for future studies towards developing a novel, effective therapy for MCL.
This study aims to understand and find a new, effective way to treat blood cancer. The proposed research is relevant to public health because a better understanding of blood cancer will ultimately lead to development of more effective treatment for this disease. The project is therefore relevant to NIH?s mission to obtain fundamental knowledge about disease and apply this knowledge to improve human health.