IgG-recognizing shed tumor-associated antigens can promote tumor invasion and metastasis

Abstract

Tumors secreting glycoproteins that act as tumor-associated antigens have been described as highly invasive and metastatic. In this study, the consequences of the humoral immune response (HIR) against these antigens were investigated. Using an in vitro model of tumor cell invasion, results indicated that the invasiveness of tumor cells secreting antigenic secreted/shed tumor glycoproteins (STGP) increases in the presence of specific anti-STGP IgG, polymorphonuclear cells and monocytes. This in vitro model showed that the coincidental presence in the matrix of both STGP and specific anti-STGP IgG increases the local release of IL-1beta, IL-6 and vascular endothelial growth factor (VEGF) by stromal cells, but not by tumor cells. Using an in vivo model, the experiments show that immune-competent mice develop an anti-tumor HIR with anti-STGP IgG production. In this model, tumor growth was increased in parallel with the serum concentration of specific anti-STGP IgG. In athymic nude (nu/nu)-beige mice the same trend was observed, suggesting a T-cell-independent tumor-promoting effect induced by anti-STGP IgG. Tumor histology showed intense infiltration of IgG-positive plasma cells and lymphocytes. A severe combined immunodeficient-beige mouse-based in vivo model of tumors, experimentally infiltrated with monoclonal IgG plasmocytoma cells, showed that only specific anti-STGP-IgG-secreting cells could exacerbate tumor invasion, angiogenesis and metastasis. These results suggest that tumors shedding/secreting antigenic STGP can induce a host IgG immune response that can promote invasion and metastasis by inducing tumor infiltrating stromal cells to release proinflammatory cytokines and VEGF.

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

“…On the other hand, there is mounting evidence that B cells can also promote tumor cell invasiveness and metastasis. In one study, tumor cells producing antigenic Secreted/shed Tumor GlycoProteins (STGPs) were transplanted into immune-competent mice or mice deficient in T cells [248]. In both mouse lines, increased tumor cell invasion correlated with an increase in serum anti-STPG IgG levels and tumoral infiltration of cells of the innate and adaptive immune system.…”

Overexpression of immunoglobulin G prompts cell proliferation and inhibits cell apoptosis in human urothelial carcinoma

“…However, the biological effects of antibodies cannot be assessed from their antigen binding properties. Tumor cells secreting antigenic secreted/shed tumor glycoproteins can induce a host IgG immune response that can promote invasion and metastasis by inducing tumor infiltrating stromal cells to release proinflammatory cytokines and VEGF [18]. Although the exact mechanism of antibody enhancement of tumor growth remains unclear, it was hypothesized that antibodies may do so by blocking target epitopes on the cancer cells [19].…”

Cancer systems immunology

“…These immunosuppressive mechanisms typically occur in a manner that does not require antigen recognition by the BCR ( Shah et al, 2005 ). Yet other studies have suggested that the production of antibodies themselves may promote tumor progression and metastasis by activation of Fc Receptors (FcRs) on myeloid cells, induction of tumor-intrinsic signaling through activation of surface receptors, promotion of pro-inflammatory granulocyte responses, promotion of angiogenesis, and suppression of cellular immunity ( Qin et al, 1998 ; Pucci et al, 2016 ; Gu et al, 2019 ; Andreu et al, 2010 ; Barbera-Guillem et al, 1999 ; Nyhus et al, 2001 ; Tan and Coussens, 2007 ).…”