Molecular Diagnostics

Alteration in tumoural PD-L1 expression and stromal CD8-positive tumour-infiltrating lymphocytes after concurrent chemo-radiotherapy for non-small cell lung cancer

Abstract

Background

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.

Methods

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.

Results

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).

Conclusion

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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Acknowledgements

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.

Author information

K.Y. and F.T. participated in the study conception and design, data collection, data analysis, reviewed the paper and approved the final draft for submission. T.K., M.K., M.M. and T.K. participated in data collection, reviewed the paper and approved the final draft for submission. K.Y., T.O., M.H. and T.N. participated in data analysis, reviewed the paper and approved the final draft for submission.

Correspondence to Fumihiro Tanaka.

Ethics declarations

Competing interests

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.

Funding

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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