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Protein Expression of immune checkpoints STING and MHCII in small cell lung cancer

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Abstract

Background

SCLC is an aggressive malignancy where immunotherapies show limited efficacy. We aimed to characterize the SCLC microenvironment according to the expression patterns of SCLC subtype markers and novel immune checkpoints to identify therapeutic vulnerabilities.

Methods

We included SCLC tissue samples from 219 surgically resected, limited-stage patients in this cross-sectional study. We performed immunohistochemistry for STING and MHCII, as well as for the novel subtype markers (ASCL1, NEUROD1, POU2F3, YAP1). Moreover, we assessed CD45 + , CD8 + and CD68 + immune cell infiltration.

Results

36% of SCLC tumors showed significant stromal or intraepithelial CD45 + immune cell infiltration. These patients exhibited significantly increased overall survival (OS) (vs. patients with immune-deserted tumors). High CD8 expression was associated with increased median OS. We found STING expression on cancer-associated fibroblasts in the stroma and on T-cells and macrophages in both tumorous and stromal compartments. STING expression positively correlated with immune cell infiltration. Increased STING-positivity in tumor nests was an independent favorable prognosticator for OS. ASCL1 was the most frequently expressed subtype-specific protein. Concomitant expression of three or four subtype-defining markers was seen in 13.8% of the included samples, whereas 24.1% of the cases were classified as quadruple negative tumors. YAP1 expression was associated with increased immune infiltrates. Tumor cell MHCII expression positively correlated with immune cell infiltration and with STING- and YAP1 expressions.

Conclusions

STING and MHCII are expressed in SCLC. The majority of immune-infiltrated SCLCs exhibit increased STING expression. Immune infiltration and STING expression are prognostic in limited-stage SCLC, making STING a potential therapeutic target.

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Data availability statement

The data that supports the findings of this study are available in the supplementary material of this article.

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Acknowledgements

The authors thank the patients and the clinical teams involved. We thank Leslie Rozeboom, UCD, for her assistance in creating TMA blocks. ZL acknowledges funding from the Hungarian National Research, Development and Innovation Office (OTKA #124652 and OTKA #129664). BD acknowledges funding from the Austrian Science Fund (FWF I3522, FWF I3977 and I4677) and from the Hungarian National Research, Development and Innovation Office (KH130356; 2020-1.1.6-JÖVŐ and TKP2021-EGA-33). VL is a recipient of the Bolyai Research Scholarship of the Hungarian Academy of Sciences and the UNKP-19-4 New National Excellence Program of the Ministry for Innovation and Technology. ZM was supported by the UNKP-20-3 and UNKP-21-3 New National Excellence Program of the Ministry for Innovation and Technology of Hungary and by the Hungarian Respiratory Society (MPA #2020).

Author information

Author notes

  1. Zoltan Lohinai and Balazs Dome: these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy, Histology, and Embryology, Faculty of Medicine, Semmelweis University, Budapest, Hungary

    David Dora

  2. Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Christopher Rivard, Hui Yu, Shivaun Lueke Pickard & Fred R. Hirsch

  3. Department of Tumor Biology, National Koranyi Institute of Pulmonology, 1121, Piheno ut 1., Budapest, Hungary

    Viktoria Laszlo, Tunde Harko, Zsolt Megyesfalvi, Csongor Gerdan, Zoltan Lohinai & Balazs Dome

  4. Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Viktoria Laszlo, Zsolt Megyesfalvi, Konrad Hoetzenecker & Balazs Dome

  5. Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary

    Viktoria Laszlo, Zsolt Megyesfalvi & Balazs Dome

  6. Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary

    Csongor Gerdan

  7. Institute of Digital Health Sciences, Faculty of Public Services, Semmelweis University, Budapest, Hungary

    Elek Dinya

  8. Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Health System, New York, NY, USA

    Fred R. Hirsch

  9. Department of Translational Medicine, Lund University, Lund, Sweden

    Balazs Dome

Authors
  1. David Dora
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  2. Christopher Rivard
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  3. Hui Yu
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  4. Shivaun Lueke Pickard
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  5. Viktoria Laszlo
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  6. Tunde Harko
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  7. Zsolt Megyesfalvi
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  8. Csongor Gerdan
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  9. Elek Dinya
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  10. Konrad Hoetzenecker
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  11. Fred R. Hirsch
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  12. Zoltan Lohinai
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  13. Balazs Dome
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Contributions

Conception and design: ZL, DD. Development of methodology: ZL, DD, CR, HY, ZM. Acquisition of data: DD, CR, HY, SLP. Analysis and interpretation of data: DD, ZL, ED, KH, ZM. Administrative, technical or material support: CR, VL, TH, JM, BD, FH, ZM. Study supervision: ZL, DD, BD. Writing and reviewing the manuscript: all authors.

Corresponding authors

Correspondence to Zoltan Lohinai or Balazs Dome.

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Dora, D., Rivard, C., Yu, H. et al. Protein Expression of immune checkpoints STING and MHCII in small cell lung cancer. Cancer Immunol Immunother 72, 561–578 (2023). https://doi.org/10.1007/s00262-022-03270-w

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