Targeting mitochodrial DNA to enhance STING-mediated immunogenicity in cancer therapy

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15541
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Tanaka Kosuke 国立研究開発法人国立がん研究センター, 先端医療開発センター, 主任研究員 (50894119)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ミトコンドリアDNA / EGFR阻害薬 / EGFR遺伝子変異 / cGAS-STING / がん免疫療法 / 自然免疫応答 / Cold to Hot Tumor

Outline of Final Research Achievements

The development of immunotherapy, particularly targeting immune checkpoint inhibitors (ICIs), has revolutionized the treatment of various cancers by leveraging the inherent immune response of the patient.Despite the clinical efficacy demonstrated by ICIs as monotherapy in 10-30% of patients, a considerable proportion exhibit intrinsic resistance to these agents. This study revealed that combined inhibitors of EGFR and caspase promote mitochondrial stress, thereby enhancing immunogenicity in EGFR-mutant lung cancer. This efficacy is dependent on the activation of mtDNA-cGAS-STING signaling. Furthermore, this combination elicited immunological response in syngeneic mouse lung tumors harboring Egfr mutation. Together, targeting mtDNA dynamics through co-inhibition of EGFR and caspase represents a promising therapeutic strategy for converting 'cold to hot tumor' in EGFR-mutant lung cancer.

Free Research Field

腫瘍免疫学

Academic Significance and Societal Importance of the Research Achievements

免疫チェックポイント阻害薬（ICI）は個体の持つ本来のがん免疫を活性化することで効果を発揮するが、多くの症例において耐性を示す。がん細胞内の免疫応答を刺激することによりICIが効きにくい腫瘍（Cold Tumor）を効きやすい腫瘍（Hot Tumor）に転換できることが分かっており、「Cold to Hot Tumor」を狙った様々な免疫複合療法が現在試みられている。本研究では分子標的薬でミトコンドリアストレスを誘導することにより免疫原性を高められることが分かり、mtDNAダイナミクスをターゲットとした「Cold to Hot Tumor」を促す新たながん免疫複合療法の治療応用が期待できる。