Targeting tumor-associated macrophages with STING agonism improves the antitumor efficacy of osimertinib in a mouse model of EGFR-mutant lung cancer
IntroductionDespite the impressive clinical response rate of osimertinib, a third-generation EGFR-TKI, as a frontline treatment for patients with EGFR-mutant non-small-cell lung cancer (NSCLC) or as a salvage therapy for patients with T790M mutation, resistance to osimertinib is common in the clinic...
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1077203/full |
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| author | Ziying Lin Ziying Lin Qiwei Wang Qiwei Wang Qiwei Wang Tao Jiang Weihua Wang Jean J. Zhao Jean J. Zhao Jean J. Zhao Jean J. Zhao |
| author_facet | Ziying Lin Ziying Lin Qiwei Wang Qiwei Wang Qiwei Wang Tao Jiang Weihua Wang Jean J. Zhao Jean J. Zhao Jean J. Zhao Jean J. Zhao |
| author_sort | Ziying Lin |
| collection | DOAJ |
| description | IntroductionDespite the impressive clinical response rate of osimertinib, a third-generation EGFR-TKI, as a frontline treatment for patients with EGFR-mutant non-small-cell lung cancer (NSCLC) or as a salvage therapy for patients with T790M mutation, resistance to osimertinib is common in the clinic. The mechanisms underlying osimertinib resistance are heterogenous. While genetic mutations within EGFR or other cancer driver pathways mediated mechanisms are well-documented, the role of tumor cell and tumor immune microenvironment in mediating the response to osimertinib remains elusive.Methods and resultsHere, using a syngeneic mouse model of EGFR-mutant lung cancer, we show that tumor regression elicited by osimertinib requires activation of CD8+ T cells. However, tumor-associated macrophages (TAMs) accumulated in advanced tumors inhibit CD8+ T cell activation and diminish the response to osimertinib. These results are corroborated by analyses of clinical data. Notably, reprogramming TAMs with a systemic STING agonist MSA-2 reinvigorates antitumor immunity and leads to durable tumor regression in mice when combined with osimertinib.DiscussionOur results reveal a new mechanism of EGFR-TKI resistance and suggest a new therapeutic strategy for the treatment of EGFR-mutant tumors. |
| first_indexed | 2024-04-10T09:57:21Z |
| format | Article |
| id | doaj.art-22f0fafa89f4470d8c705527de7a45d5 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T09:57:21Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-22f0fafa89f4470d8c705527de7a45d52023-02-16T12:07:37ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-02-011410.3389/fimmu.2023.10772031077203Targeting tumor-associated macrophages with STING agonism improves the antitumor efficacy of osimertinib in a mouse model of EGFR-mutant lung cancerZiying Lin0Ziying Lin1Qiwei Wang2Qiwei Wang3Qiwei Wang4Tao Jiang5Weihua Wang6Jean J. Zhao7Jean J. Zhao8Jean J. Zhao9Jean J. Zhao10Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, United StatesDepartment of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, ChinaDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, United StatesDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United StatesBroad Institute of Harvard and MIT, Cambridge, MA, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, United StatesDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, United StatesDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United StatesBroad Institute of Harvard and MIT, Cambridge, MA, United StatesLaboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, United StatesIntroductionDespite the impressive clinical response rate of osimertinib, a third-generation EGFR-TKI, as a frontline treatment for patients with EGFR-mutant non-small-cell lung cancer (NSCLC) or as a salvage therapy for patients with T790M mutation, resistance to osimertinib is common in the clinic. The mechanisms underlying osimertinib resistance are heterogenous. While genetic mutations within EGFR or other cancer driver pathways mediated mechanisms are well-documented, the role of tumor cell and tumor immune microenvironment in mediating the response to osimertinib remains elusive.Methods and resultsHere, using a syngeneic mouse model of EGFR-mutant lung cancer, we show that tumor regression elicited by osimertinib requires activation of CD8+ T cells. However, tumor-associated macrophages (TAMs) accumulated in advanced tumors inhibit CD8+ T cell activation and diminish the response to osimertinib. These results are corroborated by analyses of clinical data. Notably, reprogramming TAMs with a systemic STING agonist MSA-2 reinvigorates antitumor immunity and leads to durable tumor regression in mice when combined with osimertinib.DiscussionOur results reveal a new mechanism of EGFR-TKI resistance and suggest a new therapeutic strategy for the treatment of EGFR-mutant tumors.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1077203/fulllung cancerEGFR-mutantOsimertinibSTING agonisttumor-associated macrophages |
| spellingShingle | Ziying Lin Ziying Lin Qiwei Wang Qiwei Wang Qiwei Wang Tao Jiang Weihua Wang Jean J. Zhao Jean J. Zhao Jean J. Zhao Jean J. Zhao Targeting tumor-associated macrophages with STING agonism improves the antitumor efficacy of osimertinib in a mouse model of EGFR-mutant lung cancer Frontiers in Immunology lung cancer EGFR-mutant Osimertinib STING agonist tumor-associated macrophages |
| title | Targeting tumor-associated macrophages with STING agonism improves the antitumor efficacy of osimertinib in a mouse model of EGFR-mutant lung cancer |
| title_full | Targeting tumor-associated macrophages with STING agonism improves the antitumor efficacy of osimertinib in a mouse model of EGFR-mutant lung cancer |
| title_fullStr | Targeting tumor-associated macrophages with STING agonism improves the antitumor efficacy of osimertinib in a mouse model of EGFR-mutant lung cancer |
| title_full_unstemmed | Targeting tumor-associated macrophages with STING agonism improves the antitumor efficacy of osimertinib in a mouse model of EGFR-mutant lung cancer |
| title_short | Targeting tumor-associated macrophages with STING agonism improves the antitumor efficacy of osimertinib in a mouse model of EGFR-mutant lung cancer |
| title_sort | targeting tumor associated macrophages with sting agonism improves the antitumor efficacy of osimertinib in a mouse model of egfr mutant lung cancer |
| topic | lung cancer EGFR-mutant Osimertinib STING agonist tumor-associated macrophages |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1077203/full |
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