MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer

Abstract

Immunotherapy has shown limited efficacy in EGFR-mutated lung cancer patients. 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. However, STING activation was restrained by the 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 co-induction 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.

Tumor intrinsic and extrinsic functions of CD73 and the adenosine pathway in lung cancer

“…MET amplification was found to be specifically associated with CD73 expression in EGFR mutant LUAD. Genetic knockout of MET in lung cancer models resulted in decreased CD73 expression therefore displaying a connection between these two pathways (67). This study links CD73 intrinsic function to extrinsic function through immune cell regulation.…”

“…Recently, multiple groups have focused on targeting the adenosine pathway in EGFR mutant NSCLC leading to swift discoveries in the recent years (26,67). Standard of care for EGFR mutant tumors are tyrosine kinase inhibitor (TKI)s (68).…”

“…Another recent report focused on the connection between MET amplification, CD73 and suppression of STING pathway in EGFR mutant tumors (67). Authors found that MET amplification induces CD73 expression and restrains the function of STING resulting in reduced T cell activation while also causing resistance to 3 rd generation EGFR TKIs.…”

Role of STING in the treatment of non-small cell lung cancer

“…MET amplification in EGFR-TKI-resistant NSCLC cells produced a broader spectrum of cellular state changes related to the induction of STING and CD73. The immunogenicity of MET-amplified EGFR-TKI-resistant cells is enhanced, and STING induction and T-cell reactivity in tumor cells are promoted by inhibiting CD73 [ 79 ]. The recent assessment of the phase II COAST clinical trial, which investigated the combination of the CD73 inhibitor oleclumab and durvalumab (anti-PD L1) for treating locally advanced NSCLC, has demonstrated potential in prolonging the overall survival of patients after radiotherapy and chemotherapy [ 81 ].This outcome is strongly linked to the activation of the STING pathway.…”

CD73: Friend or Foe in Lung Injury

“…The overexpression of CD73 has no effect on the proliferation of CD4+ and CD8+ T cells in EGFR-mutant individuals, but it is closely associated with the elevation of CD4+ FoxP3+ Treg cells [ 78 , 101 ]. Administration of anti-CD73 regent increases tumor cell death in vitro, and CD73 blockade exhibits slower tumor outgrowth and significantly increased antigen-specific CD8+ T-cell immunogenicity following treatment with pemetrexed in an EGFR-mutant lung cancer mouse model [ 30 , 102 ]. Another aspect that is worth mentioning is the lung metastases of multiple types of cancer.…”