TY - JOUR
T1 - Immunogenomic profiling of lung adenocarcinoma reveals poorly differentiated tumors are associated with an immunogenic tumor microenvironment
AU - Akhave, Neal
AU - Zhang, Jiexin
AU - Bayley, Erin
AU - Frank, Meredith
AU - Chiou, Shin Heng
AU - Behrens, Carmen
AU - Chen, Runzhe
AU - Hu, Xin
AU - Parra, Edwin Roger
AU - Lee, Won Chul
AU - Swisher, Stephen
AU - Solis, Luisa
AU - Weissferdt, Annikka
AU - Moran, Cesar
AU - Kalhor, Neda
AU - Zhang, Jianhua
AU - Scheet, Paul
AU - Vaporciyan, Ara A.
AU - Sepesi, Boris
AU - Gibbons, Don L.
AU - Heymach, John V.
AU - Lee, Jack J.
AU - Wistuba, Ignacio I.
AU - Andrew Futreal, P.
AU - Zhang, Jianjun
AU - Fujimoto, Junya
AU - Reuben, Alexandre
N1 - Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
KW - Adenocarcinoma patterns of growth
KW - Immune microenvironment
KW - Lung adenocarcinoma
KW - Multiplatform profiling
KW - Predictors of immunotherapy response
KW - Translational pathology
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UR - http://www.scopus.com/inward/citedby.url?scp=85135941499&partnerID=8YFLogxK
U2 - 10.1016/j.lungcan.2022.08.007
DO - 10.1016/j.lungcan.2022.08.007
M3 - Article
C2 - 35973335
AN - SCOPUS:85135941499
SN - 0169-5002
VL - 172
SP - 19
EP - 28
JO - Lung Cancer
JF - Lung Cancer
ER -