Immunoglobulin GM (γ marker) allotypes expressed on IgG1 as potential genetic markers of response to immune checkpoint blockade therapy.

The results of a recent comprehensive investigation-confirmed in multiple cohorts-show that patients with hepatocellular carcinoma, who favorably responded to anti-programmed cell death protein 1 (PD-1) therapy, were enriched in IgG1-producing plasma cells. The clonally expanded cells in responders also showed upregulation of IGHG1, the gene encoding the IgG1 antibodies. IgG1 expresses four GM (γ marker) allotypes: GM 1/a, GM 2/x, GM 3/f and GM 17/z. There are well-established associations between these allotypes and IgG subclass concentrations. Additionally, these determinants influence autoantibody responses to tumor-associated antigens and contribute to the antibody-dependent cellular cytotoxicity of tumors. Based on these and other observations, I hypothesize that GM allotypes expressed on IgG1 could potentially serve as genetic markers of response to anti-PD-1 and other immune checkpoint blockade therapies characterized by the skewed expansion of IgG1 plasma cells.