RESUMEN
Introduction: Relapse is common after resection of lung adenocarcinoma (LUAD). Features of the tumor microenvironment (TME) which influence postsurgical survival outcomes are poorly characterized. Here, we analyzed the TME of more than 1500 LUAD specimens to identify the relationship between B-cell infiltration and prognosis. Methods: Whole exome sequencing and bulk RNA sequencing were performed on LUADs and adjacent normal lung tissue. Relapse-free survival and overall survival (OS) were retrospectively correlated with characteristics of the tumor and TME in three data sets. Results: High B-cell content (defined as >10% B cells) was associated with improved OS in both a The Cancer Genome Atlas-resected LUAD data set (p = 0.01) and a separate institutional stage II LUAD data set (p = 0.04, median not reached versus 89.5 mo). A validation cohort consisting of pooled microarray data representing more than 1400 resected stage I to III LUADs confirmed the association between greater B-cell abundance, specifically higher B-cell expression, and longer postsurgical survival (median OS 90 versus 71 mo, p < 0.01). Relapse-free survival was longer for patients with adenocarcinomas with high B-cell content across data sets, but it did not reach statistical significance. Subcategorization of B-cell subsets indicated that high naive B-cell content was most predictive of survival. There was no correlation between programmed death-ligand 1 expression, lymphoid aggregates, or overall immune infiltrate density and survival outcomes across the cohorts. Conclusions: The growing adjuvant immunotherapy repertoire has increased the urgency for identifying prognostic and predictive biomarkers. Comprehensive profiling of more than 1500 LUADs suggests that high tumor-infiltrating B-cell content is a favorable prognostic marker.
RESUMEN
Lung cancer is the leading cause of cancer-related deaths worldwide. Surgery and chemoradiation are the standard of care in early stages of non-small cell lung cancer (NSCLC), while immunotherapy is the standard of care in late-stage NSCLC. The immune composition of the tumor microenvironment (TME) is recognized as an indicator for responsiveness to immunotherapy, although much remains unknown about its role in responsiveness to surgery or chemoradiation. In this pilot study, we characterized the NSCLC TME using mass cytometry (CyTOF) and bulk RNA sequencing (RNA-Seq) with deconvolution of RNA-Seq being performed by Kassandra, a recently published deconvolution tool. Stratification of patients based on the intratumoral abundance of B cells identified that the B-cell rich patient group had increased expression of CXCL13 and greater abundance of PD1+ CD8 T cells. The presence of B cells and PD1+ CD8 T cells correlated positively with the presence of intratumoral tertiary lymphoid structures (TLS). We then assessed the predictive and prognostic utility of these cell types and TLS within publicly available stage 3 and 4 lung adenocarcinoma (LUAD) RNA-Seq datasets. As previously described by others, pre-treatment expression of intratumoral 12-chemokine TLS gene signature is associated with progression free survival (PFS) in patients who receive treatment with immune checkpoint inhibitors (ICI). Notably and unexpectedly pre-treatment percentages of intratumoral B cells are associated with PFS in patients who receive surgery, chemotherapy, or radiation. Further studies to confirm these findings would allow for more effective patient selection for both ICI and non-ICI treatments.