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TIMEAS, a promising method for the stratification of testicular germ cell tumor patients with distinct immune microenvironment, clinical outcome and sensitivity to frontline therapies

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Abstract

Purpose

With the heterogeneous genetic background, prognosis prediction and therapeutic targets for testicular germ cell tumors (TGCTs) are still unclear. We defined the tumor immune microenvironment activation status (TIMEAS).

Methods

We collected a total of 314 TGCT patients from four cohorts, including a 48-case microarray. A nonnegative matrix factorization algorithm was applied to identify the “immune factor”, derived the top 150 weighted genes to divide patients into immune and non-immune classes, and further separated the immune class into activated and exhausted subgroups by nearest template prediction. Tumor mutant burden, gene mutation, and copy number alteration were compared with our recently developed package “MOVICS”. A random forest algorithm was performed to establish a prediction model with fewer genes. Immunohistochemistry staining was performed to identify TIMEAS in the microarray.

Results

We constructed the TIMEAS in the TCGA-TGCT cohort and further validated it in the GSE3218 and GSE99420 cohorts. The immune class contained the activated status of T-lymphocytes, B-lymphocytes, and macrophages, while Treg cells and the WNT/TGFβ signature were more activated in the immune-suppressed subgroup. Patients in the immune-exhausted subgroup had the worst prognosis, and 22.9% of patients in the immune-activated subgroup had KRAS mutations, which might stimulate the response of the immune system and lead to a favorable prognosis. The immune-exhausted group benefited more from chemotherapy, while the immune-activated subgroup responded well to anti-PD-1/PD-L1 therapy. FSCN1 was validated as the target of the immune-exhausted microenvironment by immunohistochemistry.

Conclusion

TIMEAS classification can separate TGCT patients; patients in the immune-activated subgroup could benefit more from anti-PD-L1 immunotherapy, and those in the immune-exhausted subgroup are more suitable for chemotherapy.

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Data availability

The raw data for this study were generated at the corresponding archives. Derived data supporting the findings are available from the corresponding author [LCZ] upon reasonable request.

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Acknowledgements

We greatly appreciate the patients and investigators who participated in the corresponding medical project for providing data.

Funding

This work was supported by the National Natural Science Foundation of China [grant numbers: 82170787, 82071637, 81973145]; the Supporting Project for Distinguished Young Scholars of Anhui Colleges [grant number: gxyqZD2019018]; the National Key R&D Program of China (2019YFC1711000), and the Key R&D Program of Jiangsu Province [Social Development] (BE2020694).

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Author notes

  1. Haitao Wang

    Present address: Center for Cancer Research, Clinical Research/NCI/NIH, Bethesda, MD, 20892, USA

  2. Jialin Meng, Jingjing Gao, and Xiao Li contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, The First Affiliated Hospital of Anhui Medical University, Institute of Urology, Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, 218th Jixi Road, 230022, Hefei, People’s Republic of China

    Jialin Meng, Jingjing Gao, Xiao Li, Rui Gao, Jun Zhou, Yi Liu, Zongyao Hao, Xiansheng Zhang & Chaozhao Liang

  2. State Key Laboratory of Natural Medicines, Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, 211198, Nanjing, China

    Xiaofan Lu & Fangrong Yan

  3. Cancer Center, Faculty of Health Sciences, Center for Precision Medicine Research and Training, University of Macau, SAR, Macau, People’s Republic of China

    Haitao Wang

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Contributions

Conceptualization, MJL, GJJ and LCZ; methodology, MJL, GR, LXF, and ZXS; formal analysis, MJL, LXF, YFR and WHT; writing the original draft, LX, LY and HZY; visualization, MJL, LX, LXF and WHT; funding acquisition, HZY, ZXS and LCZ; supervision, LCZ and ZXS.

Corresponding authors

Correspondence to Zongyao Hao, Xiansheng Zhang or Chaozhao Liang.

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Ethical approval for the microarray was obtained from the Ethics Committee of the First Affiliated Hospital of Anhui Medical University (PJ-2022-06-36), and patient consent for the retrospective cohorts was waived. As the other data used in this study are publicly available, no ethical approval was needed.

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Meng, J., Gao, J., Li, X. et al. TIMEAS, a promising method for the stratification of testicular germ cell tumor patients with distinct immune microenvironment, clinical outcome and sensitivity to frontline therapies. Cell Oncol. 46, 745–759 (2023). https://doi.org/10.1007/s13402-023-00781-1

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