Abstract 5943: Plasma cell repertoire in the lung cancer tumor microenvironment

Abstract Background: Post-operative recurrence in lung cancer continues to pose a major clinical challenge. B cell and plasma cell presence has been shown to correlate with improved survival and lower relapse rates in solid cancers and with improved response to checkpoint blockade. The aim of this study was to identify distinct immune cell compositions in the circulation and tumor microenvironment and make correlations with clinical and disease specific outcomes. Methods: In this study, utilizing high-dimensional deep immunophenotyping techniques (mass cytometry), multispectral immunofluorescence based imaging and bulk RNA sequencing, we explored the B cell repertoire in the circulation and tumor microenvironment in early-stage lung cancer patients undergoing radical surgical resection. Results: We demonstrate using high-dimensional deep phenotyping, clear differences in B cell composition between the circulation and the intratumoural microenvironment. Intratumoural predominant populations include plasma cells, from CD38var immature to CD138+ mature cells. B cells undergoing germinal center and follicular maturation as well as class-switched memory cells were predominantly found in the circulation. Eight key populations were significantly differentially abundant between compartments on generalized linear mixed modelling (p<0.0001 with BH correction). These differences were observed in an external validation set. Plasma cell infiltration existed on a phenotypic spectrum from natural regulatory suppressive cells to antibody producing effector phenotypes. The latter correlating with better outcomes. Higher B cell expression of CD138 and Ig was noted within the tumor microenvironment in patients who did not experience early relapse. Significantly higher levels of circulating ki67+ CD27hi CD38hi CD95hi IL10int plasmablasts were noted in recurrence patients (p=0.02). Geospatial mapping identified clusters of suppressive plasma cells localized to the tumor stroma, likely regulating entry of effector cells into the tumor nest. Conclusions: Our data has demonstrated the unique roles of effector and suppressive B cell subsets in NSCLC and the clear difference in surrogacy between tissue compartments. The lesser infiltration of suppressive phenotypes into the tumor nest may be to prevent the subsequent infiltration of effector plasma and effector B cells into the tumor nest. This tumor line of defense would be in keeping with the observation that higher levels of suppressive B cell subsets in the circulation links to higher rates of recurrence and a higher tumor effector plasma cell infiltrate correlates with protection against recurrent disease. The ambiguous role of B cells in the tumor environment predetermines the multidirectional development of immunotherapeutic approaches, either supporting positive B cell types or inhibiting the suppressive B cell phenotypes. Citation Format: Akshay J. Patel, Naeem Khan, Alex G. Richter, Babu Naidu, Mark T. Drayson, Gary W. Middleton. Plasma cell repertoire in the lung cancer tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5943.