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Hypoxia and anaerobic metabolism relate with immunologically cold breast cancer and poor prognosis

  • Preclinical study
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Abstract

Purpose

Hypoxia-Inducible Factor HIF1α and lactate dehydrogenase LDHA drive anaerobic tumor metabolism and define clinical aggressiveness. We investigated their expression in breast cancer and their role in immune response and prognosis of breast cancer.

Methods

Tissue material from 175 breast cancer patients treated in a prospective study were analyzed with immunohistochemistry for HIF1α and LDH5 expression, in parallel with the tumor-infiltrating lymphocyte TIL-density and tertiary lymphoid structure TLS-density.

Results

High LDH5 expression was noted in 48/175 tumors, and this was related to HIF1α overexpression (p < 0.0001), triple-negative TNBC histology (p = 0.01), poor disease-specific survival (p < 0.007), metastasis (p < 0.01), and locoregional recurrence (p = 0.03). High HIF1α expression, noted in 39/175 cases, was linked with low steroid receptor expression (p < 0.05), her2 overexpression (p = 0.01), poor survival (p < 0.04), and high metastasis rates (p < 0.004). High TIL-density in the invading tumor front (TILinv) was linked with low LDH5 and HIF expression (p < 0.0001) and better prognosis (p < 0.02). High TIL-density in inner tumor areas (TILinn) was significantly linked with TNBC. Multivariate analysis showed that PgR-status (p = 0.003, HR 2.99, 95% CI 1.4–6.0), TILinv (p = 0.02, HR 2.31, 95% CI 1.1–4.8), LDH5 (p = 0.01, HR 2.43, 95% CI 1.2–5.0), N-stage (p = 0.04, HR 2.42, 95% CI 1.0–5.8), T-stage (p = 0.04, HR 2.31, 95% CI 1.0–5.1), and her2 status (p = 0.05, HR 2.01, 95% CI 1.0–4.2) were independent variables defining death events.

Conclusion

Overexpression of LDH5, an event directly related to HIF1α overexpression, characterizes a third of breast tumors, which is more frequent in TNBC. Both HIF1α and LDH5 define cold breast cancer microenvironment and poor prognosis. A rational is provided to study further whether metabolic manipulations targeting HIF and LDH5 may enhance the antitumor immune response in breast cancer.

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Data availability

All tissue samples and patient data are stored in the archives of the Department of Pathology and Department of Radiotherapy and Oncology of the Democritus University of Thrace, and can become available upon reasonable request.

Abbreviations

HIF1α¨:

Hypoxia-Inducible Factor 1α

LDHA:

Lactate dehydrogenase A

TNBC:

Triple negative breast cancer

TIL:

Tumor-infiltrating lymphocytes

inv:

Invading tumor front; inn: inner tumor areas

TLS:

Tertiary lymphoid structure

PD-L1:

Programmed death-ligand 1

PD-1:

Programmed cell death protein 1

ER:

Estrogen receptor

PgR:

Progesterone receptor

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Funding

The study has been supported by the Special Account of the Democritus University of Thrace, number 8106. S.P. received a grant support from the IKY foundation.

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Authors and Affiliations

  1. Department of Pathology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece

    Alexandra Giatromanolaki & Anastasia G. Gkegka

  2. Department of Radiotherapy/Oncology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece

    Stamatia Pouliliou & Michael Koukourakis

  3. Department of Medical Oncology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece

    Eirini Biziota & Stylianos Kakolyris

Authors
  1. Alexandra Giatromanolaki
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  2. Anastasia G. Gkegka
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  3. Stamatia Pouliliou
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  4. Eirini Biziota
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  5. Stylianos Kakolyris
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  6. Michael Koukourakis
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by AG, MK, EB, and SK. Immunohistochemistry was performed by AGG and SP. The first draft of the manuscript was written by MK and AG, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Michael Koukourakis.

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The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University Hospital of Alexandroupolis (Date.26-11-2018/No11).

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Written informed consent was obtained from the parents.

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Giatromanolaki, A., Gkegka, A.G., Pouliliou, S. et al. Hypoxia and anaerobic metabolism relate with immunologically cold breast cancer and poor prognosis. Breast Cancer Res Treat 194, 13–23 (2022). https://doi.org/10.1007/s10549-022-06609-0

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