Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors

Abstract

Background Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells. Methods Using mouse models, we studied the immunological profile of mutant EGFR-driven lung tumors before and after erlotinib treatment. Results We found that erlotinib triggered the recruitment of inflammatory T cells into the lungs and increased maturation of alveolar macrophages. Interestingly, this phenotype could be recapitulated by tumor regression mediated by deprivation of the EGFR oncogene indicating that tumor regression alone was sufficient for these immunostimulatory effects. We also found that further efforts to boost the function and abundance of inflammatory cells, by combining erlotinib treatment with anti-PD-1 and/or a CD40 agonist, did not improve survival in an EGFR-driven mouse model. Conclusions Our findings lay the foundation for understanding the effects of TKIs on the tumor microenvironment and highlight the importance of investigating targeted and immuno-therapy combination strategies to treat EGFR mutant lung cancer. Electronic supplementary material The online version of this article (10.1186/s40425-019-0643-8) contains supplementary material, which is available to authorized users.

Changes in the concentration of EGFR-mutated plasma DNA in the first hours of targeted therapy allow the prediction of tumor response in patients with EGFR-driven lung cancer

“…The reduction of the tumor mass upon EGFR TKI therapy is likely to be attributed both to the cessation of cell proliferation and to the induction of programmed cell death [17,42,43]. Some data indicate that immune-related mechanisms may also contribute to the tumor shrinkage [44,45]. Use of MRI in animal experiments revealed evidence for tumor regression occurring already within 1-7 days after TKI administration [46][47][48].…”

Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy

“…In fact, anti-PD-1/PD-L1 agents are approved for EGFR mutant NSCLC, only after progression on EGFR TKIs, suggesting EGFR TKIs favorably modulate the TME with regard to anti-PD-1/PD-L1 efficacy [ 32 ]. Extensive cancer cell death following EGFR TKI treatment in EGFR mutant NSCLC models induces a high immune cell infiltration that includes dendritic cells, macrophages, and cytotoxic CD8+ T cells [ 33 ]. Clinically, patients who relapsed on first-line EGFR TKIs experienced a change in the TME that tended to be highly immunosuppressive [ 32 ].…”

The Binary Classification of Protein Kinases

“… ↓ CD3+CD4+CD25+FoxP3+ [ 14 , 15 ] Cetuximab EGFR ↑ CD4+CD39+CD25 h FoxP3+ [ 16 ] Crizotinib ALK and ALK mutations, (HGFR, c-Met) RTK, ROS1 (c-ros) and Recepteur d’Origine Nantais (RON) RTK. ↓ not available [ 17 ] Dasatinib BCR-ABL1 ↓ CD4+CD25+FoxP3+ [ 18 ] Erdafitinib FGFR ↓ CD4+CD25+FoxP3+ [ 19 ] Erlotinib EGFR ↔ CD4+ FoxP3+ [ 20 ] Gefitinib EGFR ↓ CD4+CD25+FoxP3+ [ 21 ] Ibrutinib BTK ↓ CD4+CD25+FoxP3+ [ 22 ] imatinib BCR-ABL1, c-Kit, DDR1, DDR2, CSF-1R, PDGFR-alpha, PDGFR-beta ↓ CD4+CD25+FoxP3+ [ 23 ] Lenvatinib VEGFR1, VEGFR2, VEGFR3 ↓ CD3+CD4+FoxP3+ [ 24 ] Nilotinib BCR-ABL1 ↓ …”