Nobumasa Tamura1, Yutaka Fujiwara2, Taiki Hashimoto3, Hideaki Shiraishi4, Shigehisa Kitano5, Toshio Shimizu5, Kazuyoshi Kuwano6, Noboru Yamamoto7, Noriko Motoi3. 1. Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan. 2. Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Respiratory Medicine, Mitsui Memorial Hospital, 1 Kandaizumi-cho, Chiyoda-ku, Tokyo 101-8643, Japan. Electronic address: fujiwara-yutaka@mitsuihosp.or.jp. 3. Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. 4. Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Respiratory Medicine, Mitsui Memorial Hospital, 1 Kandaizumi-cho, Chiyoda-ku, Tokyo 101-8643, Japan. 5. Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. 6. Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan. 7. Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Abstract
OBJECTIVES: Folate receptor alpha (FRα) is expressed on the cell surface, mediates its intracellular transport via receptor-mediated endocytosis, and is involved in cell division. Whether FRα could be a potential therapeutic target in FRα-expressing cancers remains unknown. Here, we retrospectively investigated the correlations between tumor FRα expression in lung adenocarcinoma (LADC) and clinicopathological features. MATERIALS AND METHODS: FRα expression was evaluated using a tissue microarray (TMA) constructed from surgical specimens of LADC and compared with clinicopathological features including the EGFR mutation status and the expressions of PD-L1, PD-L2, PD-1, CD4, CD8, CD204, and αSMA. If the proportion of positively stained tumor cells was greater than or equal to 5%, the tumor was considered to show FRα expression; if the H-score was more than or equal to 60, the tumor was considered to show high FRα expression. RESULTS: Overall, 466 TMA cores created from 233 LADC patients were evaluated: FRα-positive expression (FRα-pos)/negative (FRα-neg), 222/11; FRα high expression (FRα-HE)/low (FRα-LE), 190/43. AnEGFR mutation was present in 53.2 % of the patients. The median H-score of FRα expression, FRα-pos rate, and FRα-HE rate for EGFR mutation/wild type were 159/104 (p = 0.0002), 97.6/92.7 % (p = 0.0773), and 88.7/73.4 % (p = 0.0026), respectively. The H-scores for FRα had mild correlations with the proportion of tumor cells with positive staining for PD-L1 (r=-0.2557, p < 0.0001), the number of CD8-positive cells per square millimeter (r=-0.1767, p = 0.0069), and the area with positive staining for αSMA (r = 0.2049, p = 0.0017). No correlations were seen between FRα expression and other cancer-immunity markers. CONCLUSION: Tumor FRα expression was significantly higher in LADCs withEGFR mutation than in those with wild-type EGFR. This study suggested that FRα expression was related to cancer and microenvironment-immunity markers such as PD-L1 expression, CD8 cells, and αSMA.
OBJECTIVES: Folate receptor alpha (FRα) is expressed on the cell surface, mediates its intracellular transport via receptor-mediated endocytosis, and is involved in cell division. Whether FRα could be a potential therapeutic target in FRα-expressing cancers remains unknown. Here, we retrospectively investigated the correlations between tumor FRα expression in lung adenocarcinoma (LADC) and clinicopathological features. MATERIALS AND METHODS: FRα expression was evaluated using a tissue microarray (TMA) constructed from surgical specimens of LADC and compared with clinicopathological features including the EGFR mutation status and the expressions of PD-L1, PD-L2, PD-1, CD4, CD8, CD204, and αSMA. If the proportion of positively stained tumor cells was greater than or equal to 5%, the tumor was considered to show FRα expression; if the H-score was more than or equal to 60, the tumor was considered to show high FRα expression. RESULTS: Overall, 466 TMA cores created from 233 LADC patients were evaluated: FRα-positive expression (FRα-pos)/negative (FRα-neg), 222/11; FRα high expression (FRα-HE)/low (FRα-LE), 190/43. AnEGFR mutation was present in 53.2 % of the patients. The median H-score of FRα expression, FRα-pos rate, and FRα-HE rate for EGFR mutation/wild type were 159/104 (p = 0.0002), 97.6/92.7 % (p = 0.0773), and 88.7/73.4 % (p = 0.0026), respectively. The H-scores for FRα had mild correlations with the proportion of tumor cells with positive staining for PD-L1 (r=-0.2557, p < 0.0001), the number of CD8-positive cells per square millimeter (r=-0.1767, p = 0.0069), and the area with positive staining for αSMA (r = 0.2049, p = 0.0017). No correlations were seen between FRα expression and other cancer-immunity markers. CONCLUSION: Tumor FRα expression was significantly higher in LADCs withEGFR mutation than in those with wild-type EGFR. This study suggested that FRα expression was related to cancer and microenvironment-immunity markers such as PD-L1 expression, CD8 cells, and αSMA.