Therapeutic antibody discovery in lung tumors by B-cell receptor sequencing

Abstract

Abstract Malignancies of the lung are expected to be responsible for over 25% of all cancer-associated mortalities in the United States in 2019. Clinical treatment of lung cancer is complicated by both poor detection of early disease activity and relapse or unresponsiveness to administered therapy. Taken together, these realities of patient outcome underscore the need for alternative therapeutic strategies. Research efforts in the cancer immunology field focus primarily on T cells in the tumor microenvironment, however, there is evidence that B cells may impart a clinical benefit in patients. The formation of tertiary lymphoid structures and antibody secretion in lung tumors associate with positive clinical outcomes yet remain understudied and poorly characterized. In an effort to expand upon these observations, we isolated B cells from cryopreserved human lung cancer tissue and recovered B-cell receptor (BCR) sequences by paired heavy and light chain single cell RNA sequencing. From these experiments, we identified clonally expanded B-cell populations and convergent BCR sequences shared between different patients. We further demonstrated that recombinant antibodies derived from lung cancer patients bind cultured lung cancer cell lines in a dose-dependent manner. This preliminary data supports the notion that tumor-resident B-cells secrete functional antibodies that may additionally be tumor-reactive. Future characterization of these antibodies includes antigen identification and the measurement of in vitro and in vivo cytotoxic activity. Human patient-derived antibodies not only could serve as a novel source for therapeutic and diagnostic agents but may also help inform vaccine design in lung cancer indications.