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Genomic features reveal potential benefit of adding anti-PD-1 immunotherapy to treat non-upper aerodigestive tract natural killer/T-cell lymphoma

Leukemia volume 38, pages 829–839 (2024)Cite this article

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Abstract

Natural killer/T-cell lymphoma (NKTCL) is a highly heterogeneous disease with a poor prognosis. However, the genomic characteristics and proper treatment strategies for non-upper aerodigestive tract NKTCL (NUAT-NKTCL), a rare subtype of NKTCL, remain largely unexplored. In this study, 1589 patients newly diagnosed with NKTCL at 14 hospitals were assessed, 196 (12.3%) of whom had NUAT-NKTCL with adverse clinical characteristics and an inferior prognosis. By using whole-genome sequencing (WGS) and whole-exome sequencing (WES) data, we found strikingly different mutation profiles between upper aerodigestive tract (UAT)- and NUAT-NKTCL patients, with the latter group exhibiting significantly higher genomic instability. In the NUAT-NKTCL cohort, 128 patients received frontline P-GEMOX chemotherapy, 37 of whom also received anti-PD-1 immunotherapy. The application of anti-PD-1 significantly improved progression-free survival (3-year PFS rate 53.9% versus 17.0%, P = 0.009) and overall survival (3-year OS rate 63.7% versus 29.2%, P = 0.01) in the matched NUAT-NKTCL cohort. WES revealed frequent mutations involving immune regulation and genomic instability in immunochemotherapy responders. Our study showed distinct clinical characteristics and mutational profiles in NUAT-NKTCL compared with UAT patients and suggested adding anti-PD-1 immunotherapy in front-line treatment of NUAT-NKTCL. Further studies are needed to validate the efficacy and related biomarkers for immunochemotherapy proposed in this study.

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Fig. 1: Kaplan–Meier survival curves in patients with NKTCL stratified by disease type.
Fig. 2: Characterization of somatic mutations and tumor mutation burden in NKTCL.
Fig. 3: Mutational landscape of UAT- and NUAT-NKTCL.
Fig. 4: The copy number variation landscape in NKTCL.
Fig. 5: Survival analysis in patients with NUAT-NKTCL stratified by first-line treatments.
Fig. 6: Somatic mutations and PD-L1 expression in NUAT-NKTCL received immunochemotherapy.

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Data availability

The newly generated WES data reported in this paper have been deposited in the Genome Sequence Archive (https://ngdc.cncb.ac.cn/gsa-human) with the accession number of HRA005217. The publicly available WGS/WES data can be retrieved from The National Omics Data Encyclopedia (NODE) (http://www.biosino.org/node) with the accession number of OEP000498.

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Acknowledgements

We are grateful for all patients who enrolled in this study and donate their clinical samples. We are also very grateful to researchers who shared WGS and WES data generated in their previous studies.

Funding

This work is supported by Guangdong Science and Technology Department (2017B020227002 to T.-Y. L and 2019A1515010742 to H. H), Medical Science and Technology Foundation of Guangdong Province (No. A2021426 to Z. W), National Natural Science Foundation of China (82270198 to H.-M. H), Cancer Innovative Research Program of Sun Yat-sen University Cancer Center (CIRP-SYSUCC-0022 to T.-Y. L).

Author information

Author notes

  1. These authors contributed equally: Zegeng Chen, He Huang, Huageng Huang, Le Yu.

Authors and Affiliations

  1. Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China

    Zegeng Chen, Le Yu, Huawei Weng, Huangming Hong & Tongyu Lin

  2. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Zegeng Chen, He Huang, Huageng Huang, Zhao Wang, Zhiming Li, Yang Liang & Tongyu Lin

  3. Department of Medical Oncology, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China

    Jian Xiao

  4. Department of Medical Oncology of Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China

    Liqun Zou

  5. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, China

    Huilai Zhang

  6. Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, 530021, China

    Chaoyong Liang

  7. Hunan Cancer Hospital, The Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, 410013, China

    Hui Zhou

  8. The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450003, China

    Hongqiang Guo

  9. The Affiliated Hospital of Guizhou Medical University, Guizhou Cancer Hospital, Guiyang, 550004, China

    Tao Wu

  10. Department of Oncology, The Fifth Affiliated Hospital Sun Yat-Sen University, Zhuhai, 519000, China

    Hongyu Zhang

  11. Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430079, China

    Huijing Wu

  12. The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China

    Zhigang Peng

  13. The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China

    Linzhu Zhai

  14. Department of Medical Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China

    Xinggui Chen

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  1. Zegeng Chen
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Contributions

Tongyu Lin, Yang Liang and Huangming Hong designed and supervised the study. Zegeng Chen and He Huang performed the genomic data collection and analysis. Huageng Huang, Le Yu, Huawei Weng, and Jian Xiao helped with genomic data collection and curation. All authors provided study materials or patients, and contributed to the data interpretation and discussion. Zegeng Chen, Huangming Hong and Tongyu Lin wrote the manuscript. All authors reviewed the manuscript and approved for its submission.

Corresponding authors

Correspondence to Yang Liang, Huangming Hong or Tongyu Lin.

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The present study about human was carried out comply with the ethical standards of Helsinki Declaration II and approved by the participating hospitals.

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Chen, Z., Huang, H., Huang, H. et al. Genomic features reveal potential benefit of adding anti-PD-1 immunotherapy to treat non-upper aerodigestive tract natural killer/T-cell lymphoma. Leukemia 38, 829–839 (2024). https://doi.org/10.1038/s41375-024-02171-4

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