Yoichi Ohtaki1,2, Kyoichi Kaira3, Jun Atsumi1,2,4, Toshiteru Nagashima1,2,4, Osamu Kawashima4, Takashi Ibe5, Mitsuhiro Kamiyoshihara5, Ryoichi Onozato6, Atsushi Fujita6, Tomohiro Yazawa7, Masayuki Sugano7, Misaki Iijima1,2, Seshiru Nakazawa1,2, Kai Obayashi1,2, Takayuki Kosaka1,2, Toshiki Yajima1,2, Hiroyuki Kuwano2, Ken Shirabe2, Akira Mogi1,2, Kimihiro Shimizu1,2. 1. Division of General Thoracic Surgery, Integrative Center of General Surgery, Gunma University Hospital Maebashi, Gunma, Japan. 2. Department of General Surgical Science, Gunma University Graduate School of Medicine Maebashi, Gunma, Japan. 3. Department of Oncology Clinical Development, Gunma University Graduate School of Medicine Maebashi, Gunma, Japan. 4. Department of General Thoracic Surgery, National Hospital Organization Shibukawa Medical Center Shibukawa, Gunma, Japan. 5. Department of General Thoracic Surgery, Maebashi Red Cross Hospital Maebashi, Gunma, Japan. 6. Department of General Thoracic Surgery, Gunma Prefectural Cancer Center Ota, Gunma, Japan. 7. Department of General Thoracic Surgery, National Hospital Organization Takasaki General Medical Center Takasaki, Gunma, Japan.
Abstract
OBJECTIVES: Since large cell neuroendocrine carcinoma (LCNEC) is a relatively rare histologic type of primary lung cancer, little is known about the immunological status of patients with LCNEC. We aimed to clarify the expression and prognostic impact of programmed cell death ligand 1 (PD-L1), CD8, CD4, and Forkhead box protein P3 (Foxp3) in LCNEC. METHODS: We retrospectively analyzed PD-L1, CD8, CD4, and Foxp3 expressions in 95 surgically resected LCNEC. PD-L1 positive staining was determined in tumors with more than 1% of tumor cells stained to any intensity, and CD8, CD4, and Foxp3 positivity was determined in tumors with more than 5% of lymphocytes stained. RESULTS: Positive expression of PD-L1, CD8, CD4, and Foxp3 was observed in 70 (74%), 52 (55%), 76 (80%), and 43 (45%) tumors, respectively. The expression of PD-L1 was significantly correlated with positive lymphatic permeation. Positive correlations were mutually observed among tumor infiltrating immune cells. Univariate and multivariate analyses showed that positive pleural invasion and Foxp3 negative expression were independent unfavorable prognostic factors for overall survival (OS). Advanced pathological stage, positive pleural invasion, CD4 negative expression in cancer stroma, and Foxp3 negative expression were identified as independent unfavorable prognostic factors for recurrence free survival (RFS). CONCLUSIONS: Foxp3 positive tumor infiltrating lymphocytes (TILs) were an independent favorable prognostic factor for both OS and RFS, whereas CD4 positive TILs were an independent significant unfavorable prognostic factor for RFS. The high frequency of PD-L1 expression could support the use of anti-programmed cell death 1 antibody in the treatment of LCNEC.
OBJECTIVES: Since large cell neuroendocrine carcinoma (LCNEC) is a relatively rare histologic type of primary lung cancer, little is known about the immunological status of patients with LCNEC. We aimed to clarify the expression and prognostic impact of programmed cell death ligand 1 (PD-L1), CD8, CD4, and Forkhead box protein P3 (Foxp3) in LCNEC. METHODS: We retrospectively analyzed PD-L1, CD8, CD4, and Foxp3 expressions in 95 surgically resected LCNEC. PD-L1 positive staining was determined in tumors with more than 1% of tumor cells stained to any intensity, and CD8, CD4, and Foxp3 positivity was determined in tumors with more than 5% of lymphocytes stained. RESULTS: Positive expression of PD-L1, CD8, CD4, and Foxp3 was observed in 70 (74%), 52 (55%), 76 (80%), and 43 (45%) tumors, respectively. The expression of PD-L1 was significantly correlated with positive lymphatic permeation. Positive correlations were mutually observed among tumor infiltrating immune cells. Univariate and multivariate analyses showed that positive pleural invasion and Foxp3 negative expression were independent unfavorable prognostic factors for overall survival (OS). Advanced pathological stage, positive pleural invasion, CD4 negative expression in cancer stroma, and Foxp3 negative expression were identified as independent unfavorable prognostic factors for recurrence free survival (RFS). CONCLUSIONS:Foxp3 positive tumor infiltrating lymphocytes (TILs) were an independent favorable prognostic factor for both OS and RFS, whereas CD4 positive TILs were an independent significant unfavorable prognostic factor for RFS. The high frequency of PD-L1 expression could support the use of anti-programmed cell death 1 antibody in the treatment of LCNEC.
Authors: Wendy A Cooper; Thang Tran; Ricardo E Vilain; Jason Madore; Christina I Selinger; Maija Kohonen-Corish; PoYee Yip; Bing Yu; Sandra A O'Toole; Brian C McCaughan; Jennifer H Yearley; Lisa G Horvath; Steven Kao; Michael Boyer; Richard A Scolyer Journal: Lung Cancer Date: 2015-05-18 Impact factor: 5.705
Authors: Hossein Borghaei; Luis Paz-Ares; Leora Horn; David R Spigel; Martin Steins; Neal E Ready; Laura Q Chow; Everett E Vokes; Enriqueta Felip; Esther Holgado; Fabrice Barlesi; Martin Kohlhäufl; Oscar Arrieta; Marco Angelo Burgio; Jérôme Fayette; Hervé Lena; Elena Poddubskaya; David E Gerber; Scott N Gettinger; Charles M Rudin; Naiyer Rizvi; Lucio Crinò; George R Blumenschein; Scott J Antonia; Cécile Dorange; Christopher T Harbison; Friedrich Graf Finckenstein; Julie R Brahmer Journal: N Engl J Med Date: 2015-09-27 Impact factor: 91.245
Authors: K Azuma; K Ota; A Kawahara; S Hattori; E Iwama; T Harada; K Matsumoto; K Takayama; S Takamori; M Kage; T Hoshino; Y Nakanishi; I Okamoto Journal: Ann Oncol Date: 2014-07-09 Impact factor: 32.976