Genetic dissection of intratumor heterogeneity in lung cancer harboring driver mutations based on tumor PD-L1 expression

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17694
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Osaka International Cancer Institute
• Principal Investigator: Kunimasa Kei 地方独立行政法人大阪府立病院機構大阪国際がんセンター(研究所), その他部局等, 呼吸器内科 副部長 (30838892)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: PD-L1 / EGFR / 腫瘍内不均一性

Outline of Final Research Achievements

We investigated the association between PD-L1 expression in tumor cells and underlying genetic mutations. Surgical resection specimens were used to extract sufficient amounts of nucleic acids for analysis, and the high (Tumor proportion score (TPS):100%) and low (TPS:0%) PD-L1-expressing parts of the tumor were each laser microdissected to examine the association between PD-L1 expression heterogeneity and genetic mutations within the same tumor The association between PD-L1 heterogeneity and gene mutations within the same tumour was investigated. Analysis showed no association between PD-L1 expression heterogeneity and genetic variants, which were found to be almost identical. However, PD-L1 expression was found to be associated with the number of tumor infiltrating lymphocytes (TILs) present in the tumor, which may be related to whether or not lymphocytes can infiltrate into the tumor depending on the tumor histological type and other factors.

Free Research Field

臨床腫瘍学

Academic Significance and Societal Importance of the Research Achievements

腫瘍細胞におけるPD-L1の発現の程度は抗PD-1/PD-L1抗体薬の効果の予測因子として確立されており、ひいては本因子が予後因子にもつながる。これまで同一腫瘍組織内でPD-L1の不均一性の背景の遺伝子変異の評価を行った研究はなく、本研究により腫瘍細胞におけるPD-L1発現の制御には腫瘍自体の遺伝子変異ではなく、その他の要因が重要である可能性が示唆された。腫瘍微小環境における組織構造などが関与している可能性もあり、今後の癌免疫療法の効果を引き出すためには、腫瘍自体の変異ではなく、微小環境を標的とした治療開発、戦略が求められる。