Immunogenomic Profiling of Lung Adenocarcinoma Reveals Poorly Differentiated Tumors Are Associated With an Immunogenic Tumor Microenvironment

Authors

Neal Akhave
Jiexin Zhang
Erin Bayley
Meredith Frank
Shin-Heng Chiou
Carmen Behrens
Runzhe Chen
Xin Hu
Edwin Roger Parra
Won-Chul Lee
Stephen Swisher
Luisa Solis
Annikka Weissferdt
Cesar Moran
Neda Kalhor
Jianhua Zhang
Paul Scheet
Ara A Vaporciyan
Boris Sepesi
Don L Gibbons
John V Heymach
Jack J Lee
Ignacio I Wistuba
P Andrew Futreal
Jianjun Zhang
Junya Fujimoto
Alexandre Reuben

Publication Date

10-1-2022

Journal

Lung Cancer

Abstract

OBJECTIVES: Pathologists have routinely observed distinct histologic patterns of growth in early-stage lung adenocarcinoma (LUAD), which have been suggested to be associated with prognosis. Herein, we investigated the relationship between LUAD patterns of growth, as defined by the updated international association for the study of lung cancer (IASLC) grading criteria, and differences in the tumor immune microenvironment to identify predictors of response to immunotherapy.

METHODS: 174 resected stage I-III LUAD tumors were classified by histologic pattern of growth (i.e. solid, micropapillary, acinar, papillary, and lepidic) and then grouped as well differentiated, moderately differentiated, and poorly differentiated. Comprehensive multiplatform analysis including whole exome sequencing, gene expression profiling, immunohistochemistry, CIBERSORT, and T-cell receptor sequencing was performed and groups were compared for differences in genomic drivers, immune cell infiltrate, clonality, and survival. Finally, multivariate analysis was performed adjusting for pathologic stage and smoking status.

RESULTS: Poorly differentiated tumors demonstrated a strong association with smoking relative to moderately differentiated or well differentiated tumors. However, unlike in prior reports, poorly differentiated tumors were not associated with a worse survival after curative-intent resection. Genomic analysis revealed that poorly differentiated tumors are associated with high tumor mutation burden but showed no association with oncogenic drivers. Immune analyses revealed that poorly differentiated tumors are associated with increased T-cell clonality, expression of PD-L1, and infiltration by cytotoxic CD8 T-cells, activated CD4 T-cells, and pro-inflammatory (M1) macrophages. Finally, multivariate analysis controlling for stage and smoking status confirmed independence of immune differences between IASLC grade groups.

CONCLUSIONS: Poorly differentiated tumors, as defined by the updated IASLC grading criteria, are associated with a distinct immunogenic tumor microenvironment that predicts for therapeutic response to immune agents, including checkpoint inhibitors, and should be included in the clinical trial design of immunotherapy studies in early-stage lung adenocarcinoma.

Keywords

Adenocarcinoma, Adenocarcinoma of Lung, B7-H1 Antigen, Biomarkers, Tumor, Humans, Lung Neoplasms, Prognosis, Tumor Microenvironment

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Supplementary Materials

PMID: 35973335