Cancer-derived sialylated IgG promotes tumor immune escape by binding to Siglecs on effector T cells

Abstract

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.

Immunoglobulin Expression in Cancer Cells and Its Critical Roles in Tumorigenesis

“…Studies have shown that the antigen recognized by RP215 is an IgG molecule with aberrant glycosylation expressed by cancer cells ( 67 ). The RP215-recognized glycosylation of cancer-derived IgG was further revealed to be N-glycosylation at asparagine 162 (Asn162), located in the CH1 domain of the IgG heavy chain and carrying a sialic acid modification ( 44 , 68 ). In subsequent studies, RP215 showed more specificity than commercial anti-IgG antibodies in discriminating cancer-derived IgG from B cell-derived IgG due to its capacity to recognize the specific sialylation site of cancer-derived Ig ( 25 , 69 ).…”

“…Wang et al. ( 44 ) purified cancer-derived IgG from the tumor microenvironment and identified a large fraction of sialylated cancer-derived IgG (SIA-CIgG). Using in vitro and in vivo models, these authors demonstrated that SIA-CIgG could significantly inhibit T cell proliferation and reduce effector T cell frequencies in a dose-dependent manner.…”

“…More importantly, cancer-derived Ig is specifically expressed in cancer cells, rendering it a potentially anti-cancer therapeutic target. Specific antibodies targeting cancer-derived IgG have shown promising anti-cancer therapeutic effects in preclinical models ( 44 , 68 ). Considering its localization on cancer cell membranes, a new generation of chimeric antigen (CAR)-T cell targeting cancer-derived IgG is also worth exploring.…”

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

“…Genetic ablation or antibody blockade of Siglec-15 restores anti-tumor immunity and inhibits tumor growth in vivo [ 88 ]. A recent report showed that cancer-derived sialylated IgG in the tumor microenvironment can promote tumor immune escape by binding to Siglecs on effector CD4+ and CD8+ T cells [ 89 ].…”

Cancer‐derived IgG involved in cisplatin resistance through PTP‐BAS/Src/PDK1/AKT signaling pathway

“…RP215, an antibody which is produced by using the cell extract of OC‐3‐VGH ovarian cancer cells as antigen, was originally considered as an antibody to an unknown pan cancer marker and later confirmed as CIgG monoclonal antibody (Lee, Laflamme, Chien, & Ting, 2008). CIgG significantly correlates to cancer initiation, proliferation, and metastasis, and participates in tumor immune escape (Liao et al., 2015; Qiu et al., 2003; Wang et al., 2019; Yang et al., 2013). Moreover, patients with high CIgG expression have poor prognosis (Liu et al., 2015; Tang et al., 2018).…”