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Discovery of acquired molecular signature on immune checkpoint inhibitors in paired tumor tissues

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Background

Immune checkpoint inhibitor (ICI) has an emerging role in several types of cancer. However, the mechanisms of acquired resistance (AR) to ICI have not been elucidated yet. To identify these mechanisms, we analyzed the pre- and post-ICI paired tumor samples in patients with AR.

Methods

Six patients with renal cell carcinoma, urothelial cell carcinoma, or head and neck cancer, who showed an initial response to ICI followed by progression and had available paired tissue samples, were retrospectively analyzed. Whole exome sequencing, RNA sequencing, and multiplex immunohistochemistry were performed on pre-treatment and resistant tumor samples.

Results

The median time to AR was 370 days (range, 210 to 739). Increased expression of alternative immune checkpoints including TIM3, LAG3, and PD-1 as well as increased CD8+ tumor-infiltrating lymphocytes were observed in post-treatment tumor than in pre-treatment tumor of a renal cell carcinoma patient. In contrast, CD8+ T cells and immunosuppressive markers were all decreased at AR in another patient with human papillomavirus-positive head and neck squamous cell carcinoma. This patient had an evident APOBEC-associated signature, and the tumor mutation burden increased at AR. Resistant tumor tissue of this patient harbored a missense mutation (E542K) in PIK3CA. No significant aberrations of antigen-presenting machinery or IFN-γ pathway were detected in any patient.

Conclusions

Our study findings suggest that the observed increase in immunosuppressive markers after ICI might contribute to AR. Moreover, APOBEC-mediated PIK3CA mutagenesis might be an AR mechanism. To validate these mechanisms of AR, further studies with enough sample size are required.

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Availability of data and materials

The dataset used and/or analyzed during the current study is provided in the supplemental materials and additional materials are available from the corresponding author on reasonable request.

Abbreviations

ICI:

Immune checkpoint inhibitor

AR:

Acquired resistance

PD-L1:

Programmed death-ligand 1

TMB:

Tumor mutational burden

PD-1:

Programmed cell death protein 1

FFPE:

Formalin-fixed and paraffin-embedded

LAG3:

Lymphocyte-activation gene 3

TIM3:

T cell immunoglobulin and mucin-domain containing-3

HLA:

Human Leukocyte Antigen

DAPI:

4′,6-diamidino-2-phenylindole

WES:

Whole Exome Sequencing

RNA-seq:

RNA sequencing

FPKM:

Fragments per kilobase million

DEG:

Differentially expressed genes

HNSCC:

Head and neck squamous cell carcinoma

TIL:

Tumor-infiltrating lymphocyte

APOBEC:

Apolipoprotein B mRNA editing catalytic polypeptide-like

HPV:

Human papillomavirus

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Acknowledgements

This study was supported by a grant of the Korea Health Technology R&D Project “Strategic Center of Cell and Bio Therapy for Heart, Diabetes & Cancer” through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (MHW), Republic of Korea (grant number : HI17C2085). This study was also supported by Seoul National University Hospital Research Fund (No. 03-2015-0380).

Funding

This study was supported by a grant of the Korea Health Technology R&D Project “Strategic Center of Cell and Bio Therapy for Heart, Diabetes & Cancer” through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (MHW), Republic of Korea (Grant Number: HI17C2085). This study was also supported by Seoul National University Hospital Research Fund (No. 03-2015-0380).

Author information

Author notes

  1. Shin Hye Yoo and Jihui Yun have contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea

    Shin Hye Yoo, Bhumsuk Keam, Chan-Young Ock, Miso Kim, Tae Min Kim, Dong-Wan Kim & Dae Seog Heo

  2. Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea

    Jihui Yun, Seung-Pyo Hong & Jong-Il Kim

  3. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea

    Jihui Yun, Seung-Pyo Hong & Jong-Il Kim

  4. Seoul National University Cancer Research Institute, Seoul, Korea

    Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Jong-Il Kim & Dae Seog Heo

  5. Department of Pathology, Seoul National University Hospital, Seoul, Korea

    Jaemoon Koh, Sehui Kim, Yoon Kyung Jeon & Kyeong Cheon Jung

  6. Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea

    Jong-Il Kim

  7. Department of Clinical Medical Sciences, Seoul National University College of Medicine, Seoul, Korea

    Shin Hye Yoo & Dae Seog Heo

Authors
  1. Shin Hye Yoo
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  2. Jihui Yun
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  3. Bhumsuk Keam
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  4. Seung-Pyo Hong
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  5. Chan-Young Ock
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  6. Jaemoon Koh
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  7. Sehui Kim
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  8. Yoon Kyung Jeon
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  9. Kyeong Cheon Jung
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  10. Miso Kim
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  11. Tae Min Kim
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  12. Dong-Wan Kim
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  13. Jong-Il Kim
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  14. Dae Seog Heo
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Contributions

Conception and design: SHY, BK, CYO; Development of methodology: SHY, JY, BK, CYO, JIK; Acquisition of data: BK, MK, TMK, DWK, DSH; Analysis and interpretation of data: SHY, JY, SPH, BK, CYO, JK, SK; Administrative, technical, or material support: BK, YKJ, KCJ, JIK; Study supervision: BK, DSH; All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bhumsuk Keam.

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Competing interest

The authors report no conflict of interest.

Ethics approval and consent to participate

The study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Hospital (no. H-1809-144-978 and H-1506-092-681). We conducted the study in accordance with the Principles of the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study.

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Patients signed informed consent regarding publishing their data and photographs.

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Yoo, S.H., Yun, J., Keam, B. et al. Discovery of acquired molecular signature on immune checkpoint inhibitors in paired tumor tissues. Cancer Immunol Immunother 70, 1755–1769 (2021). https://doi.org/10.1007/s00262-020-02799-y

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  • DOI: https://doi.org/10.1007/s00262-020-02799-y

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