Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.
The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition.


CONCLUSIONS
We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non-cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape.
Departments of 1Medicine and 2Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute; 3Harvard Medical School; 4Ludwig Institute for Cancer Research; 5Department of Neurosurgery, Massachusetts General Hospital; 6Belfer Institute for Applied Cancer Science; 7Department of Pathology, Brigham and Women's Hospital, Boston; 8Broad Institute, Cambridge, Massachusetts; 9UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and 10Department of Molecular Pharmacology and Therapeutics, Oncology Institute, Loyola University, Chicago, Illinois; 11Department of Physiology, University of Valencia, Valencia, Spain.
Esra A
EA
Akbay
Shohei
S
Koyama
Julian
J
Carretero
Abigail
A
Altabef
Jeremy H
JH
Tchaicha
Camilla L
CL
Christensen
Oliver R
OR
Mikse
Andrew D
AD
Cherniack
Ellen M
EM
Beauchamp
Trevor J
TJ
Pugh
Matthew D
MD
Wilkerson
Peter E
PE
Fecci
Mohit
M
Butaney
Jacob B
JB
Reibel
Margaret
M
Soucheray
Travis J
TJ
Cohoon
Pasi A
PA
Janne
Matthew
M
Meyerson
D Neil
DN
Hayes
Geoffrey I
GI
Shapiro
Takeshi
T
Shimamura
Lynette M
LM
Sholl
Scott J
SJ
Rodig
Gordon J
GJ
Freeman
Peter S
PS
Hammerman
Glenn
G
Dranoff
Kwok-Kin
KK
Wong
D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009857:Oncogenes; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D019139:Tumor Escape; D059016:Tumor Microenvironment
D060890:B7-H1 Antigen; D016207:Cytokines; D061026:Programmed Cell Death 1 Receptor; D066246:ErbB Receptors