Blocking plasma cell fate enhances antigen-specific presentation by B cells to boost anti-tumor immunity. Blocking plasma cell fate enhances antigen-specific presentation by B cells to boost anti-tumor immunity

B cells engage in anti-tumor immunity but how they contribute to cancer suppression remains unclear. We found that inhibiting plasma cell differentiation either in IgMi mice lacking Igh elements needed for antibody secretion or in mice with B cell-specific knockout of Blimp-1 (Blimp-1 BcKO) promoted rather than inhibited antitumor immunity and increased numbers of activated B cells. Deficiency of Blimp-1 in tumor-infiltrating B cells generated a unique transcription profile associated with expansion of mutated clones targeting cognate tumor cells. Major histocompatibility complex class II (MHC II) was required for the anti-tumor efficacy. Blimp-1-deficient B cells had increased expression of CD80 and CD86 costimulatory molecules that enhanced effector T cell function. The Blimp-1 inhibitor valproic acid suppressed tumor growth in a B cell-dependent manner. Thus, inhibition of plasma cell differentiation results in enhanced tumor-specific antigen presentation by B cells and thereby tumor repression, suggesting a potential avenue of immunotherapy against cancer. Overall design: To explore the dynamics of tumor-infiltrating B cells, we generated single-cell RNA and B cell V(D)J libraries using a combination of sorted CD138+ and B220+ B cells from tumor-infiltrating lymphocytes (TILs) that were isolated from inoculated MC38 tumors on day 18 post-inoculation (DPI18).

B细胞参与抗肿瘤免疫，但其促进癌症抑制的具体机制仍未阐明。我们发现，在缺乏抗体分泌所需Igh元件的IgMi小鼠，或是B细胞特异性敲除Blimp-1（Blimp-1 BcKO）的小鼠中，抑制浆细胞分化非但未抑制抗肿瘤免疫，反而增强了该免疫应答，并提升了活化B细胞的数量。肿瘤浸润性B细胞中Blimp-1的缺失，会形成一种独特的转录谱，该谱与靶向同源肿瘤细胞的突变克隆扩增密切相关。主要组织相容性复合体II类（MHC II）是该抗肿瘤效应得以发挥的必要条件。Blimp-1缺陷型B细胞的CD80与CD86共刺激分子表达上调，可有效增强效应T细胞的功能。Blimp-1抑制剂丙戊酸可通过B细胞依赖的方式抑制肿瘤生长。综上，抑制浆细胞分化可增强B细胞的肿瘤特异性抗原呈递能力，进而实现肿瘤抑制，这为癌症免疫治疗提供了潜在的可行策略。实验整体设计：为探究肿瘤浸润性B细胞的动态变化，我们于接种后第18天（DPI18）从接种MC38肿瘤的小鼠体内分离肿瘤浸润淋巴细胞（tumor-infiltrating lymphocytes, TILs），并通过分选CD138+与B220+ B细胞，构建了单细胞RNA测序文库与B细胞V(D)J文库。