L2pB1 Cells Contribute to Tumor Growth Inhibition

Abstract

Natural IgM (nIgM) antibodies play critical roles in cancer immunosurveillance. However, the role of B-1 B cells, the lymphocytes that produce nIgM, remains to be elucidated. L2pB1 cells, a subpopulation of B-1 B cells, have a unique poly-self-reactive nIgM repertoire and are capable of phagocytosis, potent antigen presentation, and immunomodulation. Using an inducible knock-in and knockout mouse model, we investigated the effect of the loss of L2pB1 cells in a B16F10 melanoma model. Our results show active tumor infiltration of L2pB1 cells in wild type mice, and conversely, depletion of L2pB1 cells results in larger tumor mass and increased angiogenesis. In vitro analysis revealed that L2pB1 cells contribute to the growth inhibition of melanoma cells in both 2D cell culture and 3D tumor spheroids. Similar effects were observed in an MC38 murine colon cancer model. Moreover, our data suggest that one of the ways that L2pB1 cells can induce tumor cell death is via lipoptosis. Lastly, we tested whether L2pB1 cell-derived monoclonal nIgM antibodies can specifically recognize tumor spheroids. Nine of the 28 nIgM-secreting L2pB1 clones demonstrated specific binding to tumor spheroids but did not bind control murine embryonic fibroblasts. Our study provides evidence that L2pB1 cells contribute to cancer immunity through their unique nIgM repertoire, tumor recognition, and lipoptosis. Taken together, because of their ability to recognize common features of tumors that are independent of genetic mutations, L2pB1 cells and their nIgM could be potential candidates for cancer treatment that can overcome tumor heterogeneity-associated drug resistance.

Human B-1 cells are important contributors to the naturally-occurring IgM pool against the tumor-associated ganglioside Neu5GcGM3

“…NAbs play a fundamental role in the defense against infectious pathogens ( 24 – 26 ) and in the elimination of noxious structures like dead cells and oxidized epitopes ( 27 , 28 ). Some NAbs are also able to eliminate tumor cells ( 19 , 20 , 29 ), pointing to a relevant role for these immunoglobulins and the B-1 cells secreting them in the defense against malignant transformations. Neu5GcGM3 ganglioside is not only overexpressed in several human tumors, but is also relevant for tumor biology ( 30 ) and exerts an immunosuppressive effect that promotes tumor growth ( 31 , 32 ).…”

“…A group of recent reports described a protective role for natural, tumor-reactive IgM secreted by B-1a cells in a mouse model of peritoneal carcinomatosis (17,18). Also, monoclonal IgM antibodies derived from B-1 cells expressing PD-L2 bind and induce cell death of a colon cancer cell line (19). Rawat et al suggested that NAbs play an important role in the elimination of neoantigen-expressing cells, and consequently in anti-tumor immunity (20).…”

The role of B-1 cells in cancer progression and anti-tumor immunity

“…The study demonstrated that B-1 cells expressing PD-L1 and PD-L2 can suppress T cells in response to cognate allostimulation ( 125 ). However, in tumor models, PD-L2-positive B-1 cells seem to play an anti-tumoral role rather than an immunosuppressive function ( 74 ). This effect will be further discussed in the following section.…”

“…L2pB1 cells actively accumulate within MB16F10 melanoma tumors and their depletion promotes tumor growth and angiogenesis. Moreover, L2pB1 cells secrete IgM antibodies that can bind to both B16F10 melanoma cells and MC38 colon cancer tumor spheroids, leading to tumor apoptosis ( 74 ). The involvement of L2pB1 cells in cancer immunosurveillance may have broader implications beyond the production of tumor-reactive natural IgM alone.…”

Exosomes: A potential tool for immunotherapy of ovarian cancer

“…B cells are the second adaptive immune cell population found in TME ( 194 , 195 ). B cells have been known to be carcinogenic for decades, but recent studies have linked their presence to improved prognosis in patients with cancer ( 196 ).…”