@article {1656923,
	title = {MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer},
	journal = {Cancer Res},
	volume = {82},
	number = {21},
	year = {2022},
	month = {2022 11 02},
	pages = {4079-4092},
	abstract = {Immunotherapy has shown limited efficacy in patients with EGFR-mutated lung cancer. Efforts to enhance the immunogenicity of EGFR-mutated lung cancer have been unsuccessful to date. Here, we discover that MET amplification, the most common mechanism of resistance to third-generation EGFR tyrosine kinase inhibitors (TKI), activates tumor cell STING, an emerging determinant of cancer immunogenicity (1). However, STING activation was restrained by ectonucleosidase CD73, which is induced in MET-amplified, EGFR-TKI-resistant cells. Systematic genomic analyses and cell line studies confirmed upregulation of CD73 in MET-amplified and MET-activated lung cancer contexts, which depends on coinduction of FOSL1. Pemetrexed (PEM), which is commonly used following EGFR-TKI treatment failure, was identified as an effective potentiator of STING-dependent TBK1-IRF3-STAT1 signaling in MET-amplified, EGFR-TKI-resistant cells. However, PEM treatment also induced adenosine production, which inhibited T-cell responsiveness. In an allogenic humanized mouse model, CD73 deletion enhanced immunogenicity of MET-amplified, EGFR-TKI-resistant cells, and PEM treatment promoted robust responses regardless of CD73 status. Using a physiologic antigen recognition model, inactivation of CD73 significantly increased antigen-specific CD8+ T-cell immunogenicity following PEM treatment. These data reveal that combined PEM and CD73 inhibition can co-opt tumor cell STING induction in TKI-resistant EGFR-mutated lung cancers and promote immunogenicity.

SIGNIFICANCE: MET amplification upregulates CD73 to suppress tumor cell STING induction and T-cell responsiveness in TKI-resistant, EGFR-mutated lung cancer, identifying a strategy to enhance immunogenicity and improve treatment.},
	keywords = {5{\textquoteright}-Nucleotidase, Animals, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Drug Resistance, Neoplasm, ErbB Receptors, Gene Amplification, Lung Neoplasms, Mice, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-met},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-22-0770},
	author = {Yoshida, Ryohei and Saigi, Maria and Tani, Tetsuo and Springer, Benjamin F and Shibata, Hirofumi and Kitajima, Shunsuke and Mahadevan, Navin R and Campisi, Marco and Kim, William and Kobayashi, Yoshihisa and Thai, Tran C and Haratani, Koji and Yamamoto, Yurie and Sundararaman, Shriram K and Knelson, Erik H and Vajdi, Amir and Canadas, Israel and Uppaluri, Ravindra and Paweletz, Cloud P and Miret, Juan J and Lizotte, Patrick H and Gokhale, Prafulla C and J{\"a}nne, Pasi A and Barbie, David A}
}
