Intratumoral Plasma Cells Predict Outcomes to PD-L1 Blockade in Non-small Cell Lung Cancer
Summary
Inhibitory agents targeting the programmed cell death-1 (PD-1/PD-L1) signaling axis have been sanctioned for the treatment of non-small cell lung cancer (NSCLC) patients, predicated on the substantial overall survival (OS) advantage they confer. Through transcriptomic scrutiny of 891 NSCLC tumors derived from patients administered either the PD-L1 inhibitor atezolizumab or chemotherapy in two extensive randomized clinical trials, a significant association between B cell presence and protracted OS with PD-L1 blockade is discerned, irrespective of CD8+ T cell signals. Subsequently, gene signatures representing the predominant B cell subsets extant in NSCLC are extrapolated from single-cell RNA sequencing (RNA-seq) data. Notably, augmented plasma cell signatures are discovered to be prognostic of OS in patients treated with atezolizumab, albeit not in those subjected to chemotherapy. B and plasma cells are additionally correlated with the existence of tertiary lymphoid structures and organized lymphoid aggregates. These findings insinuate a critical contribution of B and plasma cells to the efficacy of PD-L1 blockade in NSCLC.
Fig.1 Graphical abstract. (Patil, 2022)
Research Criteria
Transcriptomic analysis of NSCLC tumors from patients treated with either the PD-L1 inhibitor atezolizumab or chemotherapy from 2 large randomized clinical trials, followed by derivation of gene signatures corresponding to the dominant B cell subsets present in NSCLC from single cell RNA sequencing data.
Sample Type
Lung and peripheral tissue from NSCLC patients.
Result—Identification of B Cell Subsets by Single-Cell RNA-Seq
In an endeavor to further delineate the B cell compartment implicated in response to atezolizumab, a comprehensive analysis of a substantial scRNA-seq dataset comprising 208,506 cells obtained from lung and peripheral tissues of 44 NSCLC patients was conducted, with a focus on B and plasma cell populations. Dimensionality reduction employing uniform manifold approximation and projection (UMAP) and graph-based clustering led to the identification of three principal CD79A+ B cell subsets within tumors, namely follicular B cells, germinal center (GC) B cells, and plasma cells. Upon examination, it was discerned that the composition of these B cell subsets remained consistent between tumor and normal adjacent tissue (NAT) from the same patient, despite an increased presence of B and plasma cells in the tumor tissue. Through the investigation of transcriptional signatures specific to each subset, we were able to confirm the presence of these three populations at the protein level utilizing mass cytometry. Consequently, the study delineated expression signatures consistently identifying follicular B cells, plasma cells, and GC B cells across three independent NSCLC scRNA-seq datasets, providing critical insight into the B cell compartment involved in response to atezolizumab treatment.
Fig.2 Identification of three B cell subsets in NSCLC tumors. (Patil, 2022)
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Reference
- Patil, N.S.; et al. Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell lung cancer. Cancer Cell. 2022, 40(3): 289-300.
