Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell lung cancer
Namrata S Patil1, Barzin Y Nabet1, Sören Müller2
1Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.
Abstract:
Inhibitors of the programmed cell death-1 (PD-1/PD-L1) signaling axis are approved to treat non-small cell lung cancer (NSCLC) patients, based on their significant overall survival (OS) benefit. Using transcriptomic analysis of 891 NSCLC tumors from patients treated with either the PD-L1 inhibitor atezolizumab or chemotherapy from two large randomized clinical trials, we find a significant B cell association with extended OS with PD-L1 blockade, independent of CD8+ T cell signals. We then derive gene signatures corresponding to the dominant B cell subsets present in NSCLC from single-cell RNA sequencing (RNA-seq) data. Importantly, we find increased plasma cell signatures to be predictive of OS in patients treated with atezolizumab, but not chemotherapy. B and plasma cells are also associated with the presence of tertiary lymphoid structures and organized lymphoid aggregates. Our results suggest an important contribution of B and plasma cells to the efficacy of PD-L1 blockade in NSCLC.
Insights
B cells, particularly plasma cells, are linked to longer survival in non-small cell lung cancer (NSCLC) patients treated with PD-L1 blockade. This finding is independent of T cell activity and suggests B cells enhance immunotherapy effectiveness.
Area of Science:
- Immunology
- Oncology
- Translational Research
Background:
- Programmed cell death-1 (PD-1/PD-L1) inhibitors improve survival in non-small cell lung cancer (NSCLC).
- The role of B cells in PD-1/PD-L1 blockade efficacy is not fully understood.
Purpose of the Study:
- To investigate the association between B cell subsets and overall survival (OS) in NSCLC patients treated with PD-L1 inhibitors.
- To identify B cell-related biomarkers predictive of response to atezolizumab.
Main Methods:
- Transcriptomic analysis of 891 NSCLC tumors from patients in clinical trials treated with atezolizumab or chemotherapy.
- Derivation of gene signatures for B cell subsets using single-cell RNA sequencing (RNA-seq) data.
- Correlation analysis between gene signatures, B cell presence, tertiary lymphoid structures, and overall survival.
Main Results:
- B cell presence, independent of CD8+ T cells, was significantly associated with extended OS in patients receiving PD-L1 blockade.
- Increased plasma cell gene signatures predicted improved OS in atezolizumab-treated patients, but not chemotherapy-treated patients.
- B and plasma cells correlated with tertiary lymphoid structures and lymphoid aggregates.
Conclusions:
- B cells, especially plasma cells, play a crucial role in the efficacy of PD-L1 blockade in NSCLC.
- Plasma cell signatures may serve as predictive biomarkers for atezolizumab treatment in NSCLC.
- These findings highlight the importance of B cell-mediated immunity in anti-PD-L1 therapy response.
