Consolidation treatment with an anti-PD-L1 antibody, durvalumab, following concurrent chemo-radiotherapy (cCRT) has become a new standard of care for locally advanced non-small cell lung cancer (NSCLC). The rationale of PD-L1 blockade after cCRT is based on preclinical evidence suggesting that chemotherapy and radiotherapy up-regulate tumoural PD-L1 expression, which has not been shown in clinical studies.
To examine alteration in tumoural PD-L1 expression (tumour proportion score, TPS) and density of stromal CD8-positive tumour-infiltrating lymphocytes (CD8 + TILs) after cCRT, paired NSCLC samples obtained before and after cCRT were reviewed in comparison with those obtained before and after drug therapy.
PD-L1 expression was significantly up-regulated after cCRT (median TPS, 1.0 at baseline versus 48.0 after cCRT; P < 0.001), but not after drug therapy. There was no significant correlation between baseline TPS and post-cCRT TPS. CD8 + TIL density was significantly increased after cCRT (median, 10.6 versus 39.1; P < 0.001), and higher post-cCRT CD8 + TIL density was associated with a higher pathologic response and with a favourable survival (P = 0.019).
Tumoural PD-L1 expression was up-regulated after cCRT, which provides pathologic rationale for PD-L1 blockade following cCRT to improve prognosis. Stromal CD8 + TIL density was also increased after cCRT, and higher post-cCRT CD8 + TIL density was a favourable prognostic indicator.
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Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 68, 7–30 (2018).
Aupérin, A., Le Péchoux, C., Rolland, E., Curran, W. J., Furuse, K., Fournel, P. et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J. Clin. Oncol. 28, 2181–2190 (2010).
Antonia, S. J., Villegas, A., Daniel, D., Curran, W. J., Furuse, K., Fournel, P. et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N. Engl. J. Med. 377, 1919–1929 (2017).
Antonia, S. J., Villegas, A., Daniel, D., Vicente, D., Murakami, S., Hui, R. et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med. 379, 2342–2350 (2018).
Brahmer, J. R., Govindan, R., Anders, R. A., Antonia, S. J., Sagorsky, S., Davies, M. J. et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment non-small cell lung cancer (NSCLC). J. Immunother. Cancer 6, 75 (2018).
Zhang, P., Su, D. M., Liang, M. & Fu, J. Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Mol. Immunol. 45, 1470–1476 (2008).
Deng, L., Liang, H., Burnette, B., Beckett, M., Darga, T., Weichselbaum, R. R. et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124, 687–695 (2014).
Dovedi, S. J., Adlard, A. L., Lipowska-Bhalla, G., McKenna, C., Jones, S., Cheadle, E. J. et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 74, 5458–5468 (2014).
Fujimoto, D., Uehara, K., Sato, Y., Sakanoue, I., Ito, M., Teraoka, S. et al. Alteration of PD-L1 expression and its prognostic impact after concurrent chemoradiation therapy in non-small cell lung cancer patients. Sci. Rep. 7, 11373 (2017).
Goldstraw, P., Chansky, K., Crowley, J., Rami-Porta, R., Asamura, H., Eberhardt, W. E. et al. The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J. Thorac. Oncol. 11, 39–51 (2016).
Tanaka, F., Yokomise, H., Soejima, T., Uramoto, H., Yamanaka, T., Nakagawa, K. et al. Induction chemoradiotherapy (50 Gy), followed by resection, for stage IIIA-N2 non-small cell lung cancer. Ann. Thorac. Surg. 106, 1018–1024 (2018).
Rimm, D. L., Han, G., Taube, J. M., Yi, E. S., Bridge, J. A., Flieder, D. B. et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol. 3, 1051–1058 (2017).
Hirai, A., Yoneda, K., Shimajiri, S., Kuroda, K., Hanagiri, T., Fujino, Y. et al. Prognostic impact of programmed death-ligand 1 expression in correlation with human leukocyte antigen class I expression status in stage I adenocarcinoma of the lung. J. Thorac. Cardiovasc Surg. 155, 382–392 (2018).
Donnem, T., Hald, S. M., Paulsen, E. E., Richardsen, E., Al-Saad, S., Kilvaer, T. K. et al. Stromal CD8+T-cell density—a promising supplement to TNM staging in non-small cell lung cancer. Clin. Cancer Res. 21, 2635–2643 (2015).
Klebanoff, C. A., Gattinoni, L. & Restifo, N. P. CD8þ T-cell memory in tumor immunology and immunotherapy. Immunol. Rev. 211, 214–224 (2006).
Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).
Hendry, S., Salgado, R., Gevaert, T., Russell, P. A., John, T., Thapa, B. et al. Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in melanoma, gastrointestinal tract carcinomas, non-small cell lung carcinoma and mesothelioma, endometrial and ovarian carcinomas, squamous cell carcinoma of the head and neck, genitourinary carcinomas, and primary brain tumors. Adv. Anat. Pathol. 24, 311–335 (2017).
Remark, R., Becker, C., Gomez, J. E., Damotte, D., Dieu-Nosjean, M., C. Sautès-Fridman, C. et al. The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Am. J. Respir. Crit. Care Med. 191, 377–390 (2015).
Donnem, T., Kilvaer, T. K., Andersen, S., Richardsen, E., Paulsen, E. E., Hald, S. M. et al. Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer. Ann. Oncol. 27, 225–232 (2016).
Geng, Y., Shao, Y., He, W., Hu, W., Xu, Y., Chen, J. et al. Prognostic role of tumor-infiltrating lymphocytes in lung cancer: a meta-analysis. Cell Physiol. Biochem. 37, 1560–1571 (2015).
Zeng, D. Q., Yu, Y. F., Ou, Q. Y., Li, X. Y., Zhong, R. Z., Xie, C. M. et al. Prognostic and predictive value of tumor-infiltrating lymphocytes for clinical therapeutic research in patients with non-small cell lung cancer. Oncotarget 7, 13765–13781 (2016).
Tokito, T., Azuma, K., Kawahara, A., Ishii, H., Yamada, K., Matsuo, N. et al. Predictive relevance of PD-L1 expression combined with CD8+TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Eur. J. Cancer 55, 7–14 (2016).
Takeshima, T., Chamoto, K., Wakita, D., Ohkuni, T., Togashi, Y., Shirato, H. et al. Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with Th1 cell therapy. Cancer Res. 70, 2697–2706 (2010).
Chen, H. Y., Xu, L., Li, L. F., Liu, X. X., Gao, J. X. & Bai, Y. R. Inhibiting the CD8+T cell infiltration in the tumor microenvironment after radiotherapy is an important mechanism of radioresistance. Sci. Rep. 8, 11934 (2018).
Lugade, A., Moran, J., Gerber, S., Rose, R., Frelinger, J. & Lord, E. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J. Immunol. 174, 7516–7523 (2005).
Schaue, D., Comin-Anduix, B., Ribas, A., Zhang, L., Goodglick, L., Sayre, J. W. et al. T-cell responses to survivin in cancer patients undergoing radiation therapy. Clin. Cancer Res. 14, 4883–4890 (2008).
Lee, Y., Auh, S. L., Wang, Y., Burnette, B., Wang, Y., Meng, Y. et al. Therapeutic effects of ablative radiation on local tumor require CD8+T cells: changing strategies for cancer treatment. Blood 114, 589–595 (2009).
Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).
Yu, H., Boyle, T. A., Zhou, C., Rimm, D. L. & Hirsch, F. R. PD-L1 expression in lung cancer. J. Thorac. Oncol. 11, 964–975 (2016).
Reck, M., Rodríguez-Abreu, D., Robinson, A. G., Csőszi, T., Fülöp, A., Gottfried, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. c75, 1823–1833 (2016).
Hanna, N., Johnson, D., Temin, S., Baker, S. Jr, Brahmer, J., Ellis, P. M. et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical practice guideline update. J. Clin. Oncol. 35, 3484–3515 (2017).
Soo, R. A., Chen, Z., Yan Teng, R. S., Tan, H. L., Iacopetta, B., Tai, B. C. et al. Prognostic significance of immune cells in non-small cell lung cancer: meta-analysis. Oncotarget 9, 24801–24820 (2018).
Imanishi, N., Hirai, A., Yoneda, K., Shimajiri, S., Kuwata, T., Tashima, Y. et al. Programmed death-ligand 1 (PD-L1) expression in pleomorphic carcinoma of the lung. J. Surg. Oncol. 117, 1563–1569 (2018).
We thank all doctors in the University of Occupational and Environmental Health Japan (Second Department of Surgery, Department of Respiratory Medicine, Department of Pathology and Oncology and Department of Pathology) for helpful assistance in collecting and processing clinical samples. We also thank Dr. Yoshiyuki Fujino (Professor, Department of Environmental Epidemiology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan), an expert in medical statistics, for helpful comments on statistical analyses in the study.
K.Y. reports grants from ASAHI KASEI PHARMA CORPORATION, grants and personal fees from Astellas Pharma Inc., grants and personal fees from AstraZeneca K.K., grants and personal fees from Bristol-Myers Squibb K.K., grants and personal fees from CHUGAI PHARMACEUTICAL CO., LTD., grants from DAIICHI SANKYO COMPANY, LIMITED, grants from Daiwa Securities Health Foundation, grants and personal fees from Eli Lilly Japan K.K., grants from FUJIFILM Pharma Co., Ltd., grants from Fukuda Denshi Co., Ltd., grants and personal fees from GlaxoSmithKline K.K., grants from KAKENHI (Grants-in-Aid for Scientific Research) (C), grants from KYORIN Pharmaceutical Co.,Ltd., grants from Kyowa Hakko Kirin Co., Ltd., grants from Meiji Seika, grants and personal fees from MSD K.K. a subsidiary of Merck & Co.,Inc., grants from Mylan Inc., grants from Nippon Boehringer lngelheim Co., Ltd., grants from North East, grants and personal fees from Novartis Pharma K.K., grants from ONO PHARMACEUTICAL CO., LTD., grants from Oxford Immunotec, Inc., grants and personal fees from Pfizer Inc., grants and personal fees from Shionogi & Co., Ltd., grants from Sumitomo Dainippon Pharma Co., Ltd., grants and personal fees from TAIHO Pharmaceutical Co., Ltd., grants and personal fees from Taisho Toyama Pharmaceutical Co., Ltd., grants and personal fees from TEIJIN HOME HEALTHCARE LIMITED., outside the submitted work. F.T. reports grants and personal fees from ASAHI KASEI PHARMA CO, grants from Astellas Pharma Inc., grants and personal fees from AstraZeneca K.K., personal fees from Bristol-Myers Squibb K.K., grants and personal fees from CHUGAI PHARMACEUTICAL CO., LTD., grants and personal fees from Eli Lilly Japan K.K., grants and personal fees from Kyowa Hakko Kirin Co., Ltd., grants and personal fees from MSD K.K., grants and personal fees from Novartis Pharma K.K., grants and personal fees from ONO PHARMACEUTICAL CO., LTD., personal fees from Pfizer Inc., grants and personal fees from Shionogi & Co., Ltd., grants and personal fees from TAIHO Pharmaceutical Co., Ltd., grants from Eizai Co. Ltd., grants and personal fees from Nippon Boehringer Ingelheim Co. Ltd., personal fees from Johnson & Johnson Co. Ltd., personal fees from Covidien Japan Co. Ltd., outside the submitted work. The remaining authors declare no competing interests.
Ethics approval and consent to participate
The institutional review board of the University of Occupational and Environmental Health, Japan approved the present study. This study was performed in accordance with the Declaration of Helsinki.
This study was supported in part by the Japan Society for the Promotion of Science (JSPS) [Grants-in-Aid for Scientific Research Grant Numbers 16H10697 and 16H01747], UOEH Research Grant for Promotion of Occupational Health.
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