Immuno-therapeutics Modulating B Immunity Against Cancer

Abstract

Vaccines activating B cell to mount robust antigen specific humoral immunity against foreign pathogens, like SARS-CoV-2 virus, influenza virus, human papillomavirus., have achieved tremendous clinical success. However, the roles of B cell immunity in cancer and cancer immunotherapy have been a subject of debate for several decades. B cell immunity showed anti-tumor and pro-tumor roles under different cancers and therapeutical scenarios. In this research, we focus on two aspects of B cell immunity, a) amplification of the antigen presenting function of B cell immunity to promote B/CD4 T cell crosstalk by cancer vaccine for enhanced anti-tumor immunity, and b) elimination of B regulatory cells from tumor immune microenvironment to overcome STING agonist resistance for pancreatic tumor immunotherapy. Neoantigen cancer vaccines using peptide or mRNA have shown promising anticancer efficacy in melanoma, colon and pancreatic cancer patients. Their efficacy is achieved through dendritic cell-mediated antigen presentation to activate CD4/CD8 T cell antitumor immunity. Most recent studies discovered that tumor infiltrating B cells are positively associated with better responses to anti-PD-1 immunotherapy in patients with various cancer types. However, it is unclear whether traditional B cell immunity or other B cell functions are crucial for its beneficial anticancer efficacy, while B/CD4 T cell crosstalk is essential for CD4/CD8 T cell antitumor immunity. Yet, current neoantigen vaccines using CD4/CD8 T epitopes are unable to promote B/CD4 T cell crosstalk. We designed SARS-CoV-2 B epitope-guided neoantigen cancer vaccines using peptide or mRNA to promote the crosstalk between SARS-CoV-2 B cells and tumor CD4 T cells, through B cell-mediated antigen presentation, for improving cancer immunotherapy. In addition, the immune suppression in tumors and lymph nodes, regulated by suppressive myeloid cells and regulatory B (Breg) cells, hinders the effectiveness of immunotherapy. Although STING agonists activate myeloid cells to overcome immune suppression, it expands Breg cells, conferring STING resistance in PDAC. In the second project, we discovered that blocking PI3Kγ during STING activation abolished IRF3 phosphorylation to eliminate Breg cells, while PI3Kγ inhibition sustained STING-induced IRF3 phosphorylation to preserve STING function in myeloid cells. Therefore, we developed a dual functional compound SH-273 and its albumin nanoformulation Nano-273, which stimulates STING to activate myeloid cells and inhibits PI3Kγ to eliminates Breg cells overcoming STING resistance. Nano-273 achieved systemic antitumor immunity through intravenous administration and preferential delivery to tumors and lymph nodes, which decreases Breg cells and remodels microenvironment. Nano-273, combined with anti-PD-1, extended median survival of 200 days in transgenic KPC PDAC mice (KrasG12D-P53R172H-Cre), offering potential for PDAC treatment.