A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer

Sandra Tietscher, Johanna Wagner, Tobias Anzeneder, Claus Langwieder, Martin Rees, Bettina Sobottka, Natalie Souza and Bernd Bodenmiller ()
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Sandra Tietscher: University of Zurich
Johanna Wagner: University of Zurich
Tobias Anzeneder: Patients’ Tumor Bank of Hope (PATH)
Claus Langwieder: Pathology at Josefshaus
Martin Rees: Pathology at Josefshaus
Bettina Sobottka: University Hospital Zurich and University of Zurich
Natalie Souza: University of Zurich
Bernd Bodenmiller: University of Zurich

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Immune checkpoint therapy in breast cancer remains restricted to triple negative patients, and long-term clinical benefit is rare. The primary aim of immune checkpoint blockade is to prevent or reverse exhausted T cell states, but T cell exhaustion in breast tumors is not well understood. Here, we use single-cell transcriptomics combined with imaging mass cytometry to systematically study immune environments of human breast tumors that either do or do not contain exhausted T cells, with a focus on luminal subtypes. We find that the presence of a PD-1high exhaustion-like T cell phenotype is associated with an inflammatory immune environment with a characteristic cytotoxic profile, increased myeloid cell activation, evidence for elevated immunomodulatory, chemotactic, and cytokine signaling, and accumulation of natural killer T cells. Tumors harboring exhausted-like T cells show increased expression of MHC-I on tumor cells and of CXCL13 on T cells, as well as altered spatial organization with more immature rather than mature tertiary lymphoid structures. Our data reveal fundamental differences between immune environments with and without exhausted T cells within luminal breast cancer, and show that expression of PD-1 and CXCL13 on T cells, and MHC-I – but not PD-L1 – on tumor cells are strong distinguishing features between these environments.

Date: 2023
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DOI: 10.1038/s41467-022-35238-w

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