Xiaoyan Qiu

Immunoglobulins (Igs) are found thus far only to be produced by differentiated B lymphocytes. By immunohistochemistry analysis, in situ hybridization, and laser capture microdissection-assisted single-cell PCR, we demonstrate that human cancers of epithelial origin, including carcinomas of breast, colon, liver, lung, established epithelial cancer lines, as well as some normal lung tissues, also produce IgG in both cytoplasmic and secreted forms. Furthermore, blockade of tumor-derived IgG by either antisense DNA or antihuman IgG antibody increased programmed cell death and inhibited growth of cancer cells in vitro. More importantly, administration of antihuman IgG antibody also suppressed the growth of an IgG-secreting carcinoma line in immunodeficient nude mice. Our results support a role of tumor-derived IgG as growth factor for epithelial cancers. Prevalent expression of IgG in human carcinomas and its growth-promoting functions may have important implications in growth regulation and targeted therapy of human cancers.

Traditionally, immunoglobulin (Ig) was believed to be produced by only B-lineage cells. However, increasing evidence has revealed a high level of Ig expression in cancer cells, and this Ig is named cancer-derived Ig. Further studies have shown that cancer-derived Ig shares identical basic structures with B cell-derived Ig but exhibits several distinct characteristics, including restricted variable region sequences and aberrant glycosylation. In contrast to B cell-derived Ig, which functions as an antibody in the humoral immune response, cancer-derived Ig exerts profound protumorigenic effects via multiple mechanisms, including promoting the malignant behaviors of cancer cells, mediating tumor immune escape, inducing inflammation, and activating the aggregation of platelets. Importantly, cancer-derived Ig shows promising potential for application as a diagnostic and therapeutic target in cancer patients. In this review, we summarize progress in the research area of cancer-derived Ig and discuss the perspectives of applying this novel target for the management of cancer patients.

Synovial fibroblast hyperplasia, T-cell hyperactivity, B-cell overactivation, and the self-perpetuating interactions among these cell types are major characteristics of rheumatoid arthritis (RA). The inflamed joints of RA patients are hypoxic, with upregulated expression of hypoxia-inducible factor-1α (HIF-1α) in RA synovial fibroblasts (RASFs). It remains unknown whether HIF-1α regulates interactions between RASFs and T cells and B cells. We report here that HIF-1α promotes the expression of inflammatory cytokines IL-6, IL-8, TNF-α, and IL-1β, and cell-cell contact mediators IL-15, vascular cell adhesion molecule (VCAM)-1, thrombospondin (TSP)-1, and stromal cell-derived factor (SDF)-1 in RASFs. Furthermore, HIF-1α perpetuates RASF-mediated inflammatory Th1- and Th17-cell expansion while differentially inhibiting regulatory B10 and innate-like B cells, leading to increased IFN-γ, IL-17, and IgG production and decreased protective natural IgM secretion. Our findings suggest that HIF-1α perpetuates the interactions between RASFs and T cells and B cells to induce inflammatory cytokine and autoantibody production, thus exacerbating the severity of RA. Targeting HIF-1α may provide new therapeutic strategies for overcoming this persistent disease.

It was well accepted that only B-lymphocytes and plasma cells expressed immunoglobulin (Ig) gene. However, our group and others have confirmed that non-B-cells, such as epithelial cancer cells, can also express Ig. The aim of this work is to elucidate the role of non-B-cell-derived Ig by investigating the characteristics of the Ig heavy chain (IgH) gene repertoire in epithelial cancer cells. We cloned and sequenced 89 V(H)DJ(H) (V-D-J recombination of the IgH variable region) transcripts by microdissecting cells from eight different types of epithelial cancers and two cancer cell lines (HT-29 and HeLa S3). The cancer-derived Ig gene repertoire showed specific restricted patterns of V(H)DJ(H) recombination with seven sets of predominant V(H)DJ(H) sequences. Surprisingly, within a set of V(H)DJ(H) recombination, the variable (V) sequences derived from different cancer types had not only identical heavy chain variable (VH), diversity (D), and joining (JH) segments usage, but also identical junctions and mutation targets in the V(H) region. The V(Hgamma)DJ(Hgamma) (but not V(Hmicro)DJ(Hmicro)) in the cancer-derived sequences had a high mutation rate; however, it was shown that the mechanism of hypermutation was different from antigen selection in B-cell-derived V(Hgamma)DJ(Hgamma)sequences. In contrast to V(Hmicro)DJ(Hmicro), the V(Hgamma)DJ(Hgamma) sequences did not appear to originate from classical class switching. These results suggest that cancer-derived Ig genes have a distinct repertoire that may have implications for their role in carcinogenesis.

To date, IgG in the tumor microenvironment (TME) has been considered a product of B cells and serves as an antitumor antibody. However, in this study, using a monoclonal antibody against cancer-derived IgG (Cancer-IgG), we found that cancer cells could secrete IgG into the TME. Furthermore, Cancer-IgG, which carries an abnormal sialic acid modification in the CH1 domain, directly inhibited effector T-cell proliferation and significantly promoted tumor growth by reducing CD4+ and CD8+ T-cell infiltration into tumor tissues. Mechanistic studies showed that the immunosuppressive effect of sialylated Cancer-IgG is dependent on its sialylation and binding to sialic acid-binding immunoglobulin-type lectins (Siglecs) on effector CD4+ and CD8+ T cells. Importantly, we show that several Siglecs are overexpressed on effector T cells from cancer patients, but not those from healthy donors. These findings suggest that sialylated Cancer-IgG may be a ligand for Siglecs, which may serve as potential checkpoint proteins and mediate tumor immune evasion.