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.

天然 IgM (nIgM) 抗体在癌症免疫监视中发挥着关键作用。然而，B-1 B 细胞（产生 nIgM 的淋巴细胞）的作用仍有待阐明。 L2pB1 细胞是 B-1 B 细胞的一个亚群，具有独特的多自身反应性 nIgM 库，能够进行吞噬作用、有效的抗原呈递和免疫调节。使用诱导型敲入和敲除小鼠模型，我们研究了 B16F10 黑色素瘤模型中 L2pB1 细胞缺失的影响。我们的结果显示野生型小鼠中 L2pB1 细胞的活跃肿瘤浸润，相反，L2pB1 细胞的耗竭导致更大的肿瘤块和增加的血管生成。体外分析表明，L2pB1 细胞有助于抑制 2D 细胞培养物和 3D 肿瘤球体中黑色素瘤细胞的生长。在 MC38 小鼠结肠癌模型中观察到类似的效果。此外，我们的数据表明，L2pB1 细胞诱导肿瘤细胞死亡的方式之一是通过脂肪凋亡。最后，我们测试了 L2pB1 细胞来源的单克隆 nIgM 抗体是否可以特异性识别肿瘤球体。 28 个分泌 L2pB1 克隆中的 9 个表现出与肿瘤球体的特异性结合，但不结合对照小鼠胚胎成纤维细胞。我们的研究提供的证据表明，L2pB1 细胞通过其独特的 nIgM 库、肿瘤识别和脂肪凋亡有助于癌症免疫。总而言之，由于 L2pB1 细胞及其 nIgM 能够识别独立于基因突变的肿瘤的共同特征，因此它们可能成为癌症治疗的潜在候选者，从而克服肿瘤异质性相关的耐药性。