Abstract
Human immunoglobulin G (IgG) is the primary component of the human serum antibody fraction, representing about 75% of the immunoglobulins and 10–20% of the total circulating plasma proteins. Generally, IgG sequences are highly conserved, yet the four subclasses, IgG1, IgG2, IgG3, and IgG4, differ in their physiological effector functions by binding to different IgG-Fc receptors (FcγR). Thus, despite a similarity of about 90% on the amino acid level, each subclass possesses a unique manner of antigen binding and immune complex formation. Triggering FcγR-expressing cells results in a wide range of responses, including phagocytosis, antibody-dependent cell-mediated cytotoxicity, and complement activation. Textbook knowledge implies that only B lymphocytes are capable of producing antibodies, which recognize specific antigenic structures derived from pathogens and infected endogenous or tumorigenic cells. Here, we review recent discoveries, including our own observations, about misplaced IgG expression in tumor cells. Various studies described the presence of IgG in tumor cells using immunohistology and established correlations between high antibody levels and promotion of cancer cell proliferation, invasion, and poor clinical prognosis for the respective tumor patients. Furthermore, blocking tumor-cell-derived IgG inhibited tumor cells. Tumor-cell-derived IgG might impede antigen-dependent cellular cytotoxicity by binding antigens while, at the same time, lacking the capacity for complement activation. These findings recommend tumor-cell-derived IgG as a potential therapeutic target. The observed uniqueness of Ig heavy chains expressed by tumor cells, using PCR with V(D)J rearrangement specific primers, suggests that this specific part of IgG may additionally play a role as a potential tumor marker and, thus, also qualify for the neoantigen category.
Highlights
Immunoglobulins (Ig), commonly known as antibodies, are, according to classical theory, proteins secreted by B lymphocytes (B cells), which, in turn, are dedicated to the adaptive immune system
These results indicate a wide range of tumor entities with the ability to express cancer-derived IgG (CIgG)
A point mutation in the region of this octamer element reduced the Ig transgene expression in genetically modified mice to a mere 5% of the normal level [53]. These results revealed that the octamer element for octamer-related protein-1 (Oct-1) and Oct-2 binding is present in non-B-cell cancer cell lines and is mandatory for Ig gene expression in B cells and in non-B-cell cancer cells [54]
Summary
Immunoglobulins (Ig), commonly known as antibodies, are, according to classical theory, proteins secreted by B lymphocytes (B cells), which, in turn, are dedicated to the adaptive immune system. In a few cases, the expression of whole IgG, or at least entire Ig chains, was demonstrated in noncancerous, nonlymphoid tissues, such as normal human lung and colon tissues [12,14,19] The functions of these non-lymphoid and noncancerous Igs are still unclear. Multiple myeloma is known to be derived from MGUS and possesses a 1% expression rate of some Ig types [23,24,25] The products of these malignant B cells are mostly IgG, followed by IgA, solitary free light chains (Bence Jones myeloma), and IgD; all detectable in serum or urine samples [26]. The IgH sequences of cancer cells were significantly mutated in the VH3–23 region compared to normal cells [14]
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