ABSTRACT
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 naïve 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.