Yan Tang, PhD
Pulmonary and Clinical Care Medicine
Yan Tang*, David J. Kwiatkowski
David J. Kwiatkowski
The survival of patients with resectable non–small cell lung cancer (NSCLC) has not substantially improved since the establishment of adjuvant chemotherapy as standard treatment more than 20 years ago. Inhibitors of programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are approved for the treatment of advanced-stage NSCLC and resected stage II–III, PD-L1–expressing NSCLC. These agents have shown some benefit when given prior to surgery in small (n=21–23) studies of patients with resectable NSCLC; however, the pathologic response rates in these studies have wide confidence intervals (CIs), and predictive biomarkers of response remain unclear. The phase II Lung Cancer Mutation Consortium 3 (LCMC3) study was performed to evaluate the efficacy of neoadjuvant atezolizumab, a PD-L1 inhibitor, in a large population of treatment-naïve patients with resectable, stage IB–IIIB NSCLC. In this study, 181 patients received two doses of neoadjuvant atezolizumab monotherapy. Of the 143 patients in the primary endpoint analysis, the major pathologic response (MPR; ≤10% viable malignant cells) was 20% (95% confidence interval, 14%–28%). The 3-year survival rate of 80% was encouraging. Prospective correlative studies were performed to elucidate potential predictors of treatment response and resistance. Atezolizumab is hypothesized to enhance antitumor immunity by restoring the function of cytotoxic T cells. However, a large-scale study of atezolizumab in advanced NSCLC suggests that intratumoral B cells outperforms T cells in predicting outcomes to PD-L1 blockade. Enrichment of tumor-infiltrating B and plasma cells were reported to be associated with improved overall survival in NSCLC. However, the role of B cells in immunotherapy are poorly characterized. Here, we performed paired single-cell RNA and B-cell receptor (BCR) sequencing of 17 early-stage NSCLC receiving neoadjuvant atezolizumab, and observed association of clonal expansion of plasma B cells with better response to atezolizumab.
Because not all patients respond to PD-(L)1 inhibition, identifying biomarkers predictive of response and resistance may aid in treatment selection. Moreover, elucidating the mechanisms by which cancer cells evade antitumor immunity may inform rational combination therapies. To define the clinical and biologic effects of neoadjuvant atezolizumab and to identify biomarkers predictive of response (or lack thereof), the LCMC3 study evaluated the immune environment pre- and post-treatment with atezolizumab and correlated these changes with the primary efficacy measure of major pathologic response (MPR). While previous studies suggest enrichment of tumor-infiltrating B cells in NSCLC, the role of sub-type B cell populations in immunotherapy is not well characterized. Our paired single-cell RNA and B-cell receptor (BCR) sequencing of 17 early-stage NSCLC tumors receiving neoadjuvant atezolizumab revealed heterogenous transcriptional and clonotypic states of subtypes of tumor-infiltrating B cell populations, unraveling their potential roles in pathologic response to PD-(L)1 immunotherapy in early-stage NSCLC.