Cancer-Associated B Cells in Sarcoma

Abstract

Despite being one of the first types of cancers studied that hinted at a major role of the immune system in pro- and anti-tumor biology, little is known about the immune microenvironment in sarcoma. Few types of sarcoma have shown major responses to immunotherapy, and its rarity and heterogeneity makes it challenging to study. With limited systemic treatment options, further understanding of the underlying mechanisms in sarcoma immunity may prove crucial in advancing sarcoma care. While great strides have been made in the field of immunotherapy over the last few decades, most of these efforts have focused on harnessing the T cell response, with little attention on the role B cells may play in the tumor microenvironment. A growing body of evidence suggests that B cells have both pro- and anti-tumoral effects in a large variety of cancers, and in the age of bioinformatics and multi-omic analysis, the complexity of the humoral response is just being appreciated. This review explores what is currently known about the role of B cells in sarcoma, including understanding the various B cell populations associated with sarcoma, the organization of intra-tumoral B cells in tertiary lymphoid structures, recent trials in immunotherapy in sarcoma, intra-tumoral immunoglobulin, the pro-tumor effects of B cells, and exciting future areas for research.

Keywords: B cells; sarcoma; tertiary lymphoid structures.

Figure 1

Putative effector functions of B cells in sarcoma. 1. Homing to tumor and formation of TLS: increased expression of CXCR3 in intra-tumoral B cells suggests homing to tumor via CXCR3:CXCL9/10/11 pathways [11,19]. Increased CXCL13 in the tumor microenvironment promotes the homing of B cells and follicular T helper cells via CXCR5 and formation of TLS [20]. 2. Antigen presentation, priming and activating T cell response: B cells act as professional APCs that use BCR-mediated endocytosis to process and present tumor antigens via MHC class I and II molecules to T cells [21,22]. Relatively high levels of expression of costimulatory molecules CD27, CD80, and CD86 suggest intra-tumoral B cells are potent T cell stimulators which have downstream anti-tumor effects [11,23,24]. 3. Direct effects of antibodies: differentiation of B cells into plasma cells generates antibodies with a variety of effector functions. IgG1 can opsonize tumor cells for antibody-dependent phagocytosis, antibody-dependent cellular cytotoxicity, and activation of the complement [25]. IgG4 has been hypothesized to act as a blocking antibody and inhibit IgG1 activity and is promoted by T_regs and Th2 CD4⁺ T cells [26]. IgA may act via Fc receptor-mediated effector functions such as IgG1, however, IgA-positive B cells also participate in a positive feedback loop with immunosuppressive T_regs, as TGF-β secreted by T_regs promotes IgA class switching and IgA⁺ B_regs secrete IL-10 and IL-35 [27]. IgD promotes class switching towards IgA and IgE via basophil activation. High IgE reflects increased Th2 differentiation of CD4⁺ T cells and limited differentiation towards Th1 with decreased anti-tumor, cell-mediated responses [27]. 4. Immunosuppression: B_regs may promote tumor growth by secretion of immunosuppressive cytokines that downregulate T cell effector functions and promote T_reg differentiation and proliferation. B_regs are IgA⁺ and can express PD-1, which acts to promote IL-10 production [27,28]. This may have implications for use of immune checkpoint inhibition in sarcoma treatment [28,29,30,31]. Abbreviations: CAB: cancer associated B cell; B_reg: regulatory B cell; T_reg: regulatory T cell; APC: antigen presenting cell; Tfh: T follicular helper cell; PC: plasma cell; BCR: B cell receptor, TLS: tertiary lymphoid structure. Created with BioRender.com.

Figure 2

Structure and function of mature tertiary lymphoid structures (TLS). Intra-tumoral B cells in sarcoma may be scarce and diffuse, and/or associated with organized anti-tumor immune responses within tertiary lymphoid structures. When mature, TLSs have been associated with a positive prognosis and responses to checkpoint inhibitions in sarcoma [36]. The cellular composition and structure of a mature TLSs greatly resembles that of a secondary lymphoid organ (SLO) and includes B cells that may or may not form germinal centers, follicular helper CD4⁺T cells, a populations of CD4⁺ helper T cells, CD8⁺ cytotoxic T cells, follicular dendritic cells that promote germinal center formation and memory B cell selection, mature dendritic cells that present antigens to T cells, a dense stromal network of follicular reticular cells that provides the structure for this cellular organization, and high endothelial vessels that are key in the recruitment of immune cells to the TLS. Mature TLSs in tumors also recapitulate many functional mechanisms of SLOs, with evidence of T cell activation, somatic hypermutation (SMH), class switching, differentiation of B cells into plasma cells, and memory cells. Given the lack of capsule, it is possible that improved tumor antigen sampling can result in effective anti-tumor immunity through the activation and differentiation of B and T cells in the tumor microenvironment; however, the effectiveness of these mechanisms seems to be related to the maturity of the TLS, highlighting the importance of all these complex cellular interactions in a robust anti-tumor response [17,20]. Created with BioRender.com.