Characterization of the IgG4 Repertoire and Tolerance-Associated Variants in Late Stage Melanoma – PI: Melissa Smith

It is widely accepted that T cells play a crucial role in the tumor microenvironment and anti-cancer immunity; however, the role of B cells has not well characterized. Further investigation and definition of the role B cells play in tumor environments creates a major opportunity for the development of new B-cell based immunotherapies for melanoma. Although trafficking of B cells to the tumor microenvironment has been described in melanoma, it is unknown whether this increase in B cells is antigen-specific or due to a general inflammatory response. 

Recent studies have speculated that B cells in the melanoma tumor microenvironment induce a tolerizing effect through the production of Th2-type cytokines and chemokines, as well as elevated secretion of IgG4 antibodies, resulting in a qualitatively weaker humoral response. In general, IgG4 is thought to be a weak immune activator compared to anti-tumor IgG1 antibodies, resulting in decreased antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Overall, it remains unknown whether antigen specific clonotypes are associated with melanoma disease severity and/or if IgG4-specific variants can be identified that confer the decreased effector functions observed in late stage disease.

We hypothesize that circulating IgG4 and Th2-like cytokine levels will be elevated in advanced melanoma disease and that the IgG4-specific repertoire will contain polymorphisms in key residues and posttranslational modification motifs impacting effector function. Addressing this hypothesis with current immune profiling methods would be impossible, as they provide only limited resolution of isotype identify and no definition of the Fc domain, which modulates function. The utilization of a novel IgG repertoire profiling method, full length (FL) RepSeq, will resolve the Fc domain, including unique variation in Fc that may impact antibody effector function. Definition of critical variants impacting antibody effector function, and identification of inflammatory analytes associated with this skewed response, will aid in our effort to understand the role of humoral immunity in melanoma and advance our ability to leverage IgG antibodies as part of immunotherapy approaches to treat this disease.