Impact of Bcell and antibody immune responses in patients with melanoma

Clinical outcomes in melanoma, the most aggressive skin cancer, may depend on the development of effective immune responses, which are often limited by tumour-associated suppressive mechanisms. Over recent years there has been increasing evidence for tumour-infiltrating B cells (TIL-B) acting as a positive prognostic marker of melanoma and a key predictor of patient response to treatment [2]. B cells and their expressed antibodies appear to influence tumour regulation in the melanoma microenvironment, with different isotypes associated with anti-tumour immune responses, or equally with progressive disease.

The highly immunogenic nature of melanoma is associated with the increased levels of immune cell infiltrates required for cytotoxic anti-tumour activity, which may be intensified in response to checkpoint inhibitor immunotherapy. During chronic lymphocyte activation and inflammation, tertiary lymphoid structures (TLS) may form, comprising a structured and highly specialised germinal centre-like formation of lymphocytes and dendritic cells. TLSs have been identified in a range of cancers, including 26% of metastatic melanomas, and their presence is associated with a more positive prognosis and better responses to immunotherapy [4]. Interestingly, there is increasing evidence of these TLS sites promoting B cell maturation, clonal amplification, class switching and somatic hypermutation (SHM) [2]. These suggest their importance in B cell-mediated anti-tumour activity.

There is a large variety of differentiated B cells present in melanoma tumours such as memory, plasma cells and plasmablasts (PBs), all with pro- or anti-tumour roles in the tumour microenvironment (TME) and likely within tumour-associated TLS. B cell-mediated anti-tumour activity is conferred through tumour-clearing antibody production, with antibody isotypes such as IgG1, the most immunoactive of IgGs, likely facilitating complement activation, antibody dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP). Furthermore, enhanced presentation of tumour-derived antigens and B cell activation can result in clonal amplification and isotype switching to activatory antibody production, further driving anti-tumour immune responses. In contrast, B cells can exert pro-tumour activity via expression of inflammatory antibody isotypes (such as IgG4), activation of regulatory Bcells (Breg) which can interact with and promote regulatory T cells (Treg) [5]. It has been suggested that B cells in the tumour microenvironment are pressured to develop a regulatory phenotype, leading to the production of TGFB+ and IL-10 by Tregs and Bregs respectively, and as a result directly contribute to tumour-progression [6].

This project plans to investigate the mechanisms underlying the humoral immune compartment of melanoma, dissecting the roles of B cell subsets and their expressed antibodies in the circulation of patients with melanoma and in the tumour microenvironment (TME), and placing this understanding in the context of response to checkpoint inhibitor therapy.