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

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-1(high) 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.

Automated summary

Immune checkpoint therapy in breast cancer is limited to triple negative patients and shows rare long-term clinical benefit. This study explores the immune environments of human breast tumors with or without exhausted T cells, focusing on luminal subtypes. The presence of a PD-1(high) exhaustion-like T cell phenotype is associated with an inflammatory immune environment, increased myeloid cell activation, elevated immunomodulatory and cytokine signaling, accumulation of natural killer T cells, and altered spatial organization. PD-1 and CXCL13 expression on T cells, and MHC-I expression on tumor cells are distinguishing features between the immune environments.