Unbiased high-dimensional flow cytometry identified NK and DC immune cell signature in Luminal A-type and triple negative breast cancer

ABSTRACT

Breast cancer is the most common malignancy in women worldwide and a highly heterogeneous disease. Four different subtypes are described that differ in the expression of hormone receptors as well as the growth factor receptor HER2. Treatment modalities and survival rate depend on the subtype of breast cancer. However, it is still not clear which patients benefit from immunotherapeutic approaches such as checkpoint blockade. Thus, we aimed to decipher the immune cell signature of the different breast cancer subtypes based on high-dimensional flow cytometry followed by unbiased approaches. Here, we show that the frequency of NK cells is reduced in Luminal A and B as well as triple negative breast cancer and that the phenotype of residual NK cells is changed toward regulatory CD11b⁻CD16⁻ NK cells. Further, we found higher frequencies of PD-1⁺ CD4⁺ and CD8⁺ T cells in triple negative breast cancer. Moreover, while Luminal A-type breast cancer was enriched for CD14⁺ cDC2 (named type 3 DC (DC3)), CD14⁻ cDC2 (named DC2) were more frequent in triple negative breast cancer. In contrast, HER2-enriched breast cancer did not show major alterations in the composition of the immune cell compartment in the tumor microenvironment. These findings suggest that patients with Luminal A- and B-type as well as triple negative breast cancer might benefit from immunotherapeutic approaches targeting NK cells.

KEYWORDS:

• Breast cancer
• immune cell signature
• NK cells
• PD-1
• tumor microenvironment

Acknowledgments

Funding: The study was funded by the Emerging Fields Initiative BIG-THERA to FN, TB, AM, PF, and MWB with DD as speaker and coordinator (FAU Erlangen-Nürnberg, Staedtler Stiftung). DD was funded by the German Research Foundation [Deutsche Forschungsgemeinschaft (DFG)] (DU548/5-1 420943261, TRR305-B05 429280966) and a proposal funded by the Agence Nationale de la Recherche (ANR) and the DFG (DU548/6-1 431402787). FN was funded by TRR305-B02, AH and PF were funded by TRR305-Z02 429280966, and TB received funding from TRR305-Z01 429280966.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Lukas Heger performed the experiments with the participation of Gordon F. Heidkamp and Lukas Amon. Matthias Rübner, Caroline C. Hack, Hanna Huebner, Ramona Erber, Peter Fasching, and Matthias W. Beckmann gave scientific advice and were responsible for supply with human breast cancer tissue, grading, and molecular subtype characterization. Falk Nimmerjahn, Tobias Bäuerle and Andreas Maier provided valuable scientific advice and data interpretation. Lukas Heger and Diana Dudziak analyzed the data. Lukas Heger and Diana Dudziak supervised and designed the study. Lukas Heger and Diana Dudziak wrote the manuscript with contributions from all authors.

Data availability statement

The data supporting this study are available from the corresponding authors upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2296713.

Additional information

Funding

The work was supported by the Deutsche Forschungsgemeinschaft [TRR305-B02]; Deutsche Forschungsgemeinschaft [TRR305-Z01]; Deutsche Forschungsgemeinschaft [DU548/5-1 420943261,TRR305-Z02,TRR305-B05 429280966]; Friedrich-Alexander-Universität Erlangen-Nürnberg [Emerging Fields Initiative BIG-THERA]; Agence Nationale de la Recherche and Deutsche Forschungsgemeinschaft [DU548/6-1 431402787]; Staedtler Stiftung [Emerging Fields Initiative BIG-THERA].