We have used a patented (US 8,745,713) in vitro antibody platform technology to isolate fully human antibodies against a novel B cell lymphoma secreted biomarker, which is an isoform of the Fc Receptor-Like (FCRL) protein family. The FCRL isoform appears to inhibit CD4+ T cell recognition, and consequently would obstruct T cell immunosurveillance of B cell lymphoma. Targeted antibody immunotherapy is now a first-line treatment of B cell lymphoma due to the success of rituximab, a chimeric antibody that binds to and eliminates cells expressing the pan-B cell marker CD20. We envision that antibody targeting the secreted FCRL isoform would have a completely different mechanism of action from antibodies that bind to and eliminate cells expressing tumor antigens. Instead, anti-FCRL would be more analogous to antibodies that target immunoinhibitory molecules like CTLA4, or PD1 and its ligand PD-L1. Antibodies blocking these inhibitory interactions restore T cell function, ostensibly by promoting T cell priming in the case of CTLA4 blockade, and by preventing T cell exhaustion during PD1/PD-L1 blockade. Antibody targeting the FCRL lymphoma biomarker is instead expected to boost CD4+ T cell antigen presentation by DC and other professional APC, allowing for more robust T-cell anti-tumor responses. Furthermore, targeting the secreted FCRL isoform is not expected to have serious side effects like tumor lysis syndrome, nor affect the patients’ normal B cells. Moreover, since the FCRL biomarker was identified in serum of lymphoma patients, a clinical diagnostic screening assay could readily be developed to monitor for tumor progression and treatment response, as well as, identify candidate patients for FCRL targeted antibody immunotherapy.

Sphingosine-1-phosphate (S1P), a bioactive lipid, plays important roles in tumor development through its ability to promote tumor cell growth, migration, and invasion. S1P, synthesized by sphingosine kinase 1 and 2 (SK1 and SK2), can initiate multiple signal events through intracellular and extracellular mechanisms. In human cancer patients, increased levels of S1P and SK1 are correlated with poor prognosis and high incidence of diseases recurrence. How sphingolipid signaling regulates the function of immune cells and inflammation during tumor development remains poorly understood. Our results demonstrate that sphingolipid-induced inflammasome activation and IL-1β production promotes tumorigenesis and metastasis. Interestingly, our data indicate that SK-1/S1P signaling induces inflammasome activation and IL-1 production. We found that in MMTV-PyT transgenic mouse mammary gland tumor model, genetic loss of SphK1 significantly inhibited breast cancer progression and metastasis, accompanied by reduced levels of IL-1β at primary tumors and metastatic sites. Our results further show that SK1 and S1P modulate tumor microenvironments through induction of inflammasome activation and recruitment of myeloid cells. These findings indicate that the cross-talk between the SK1/S1P and inflammasome/IL-1 pathways promotes tumor growth and metastasis.