Single-cell profiling defines the prognostic benefit of CD39high tissue resident memory CD8+ T cells in luminal-like breast cancer

Agnese Losurdo,Giorgia Alvisi,Emilia Maria Cristina Mazza,Corrado Tinterri,Clelia Peano,Armando Santoro,Massimo Roncalli,Alberto Testori,Bethania Fernandes,Valentina Errico,Jolanda Brummelman,Enrico Lugli,Federico Simone Colombo,Karolina Pilipow,Caterina Scirgolea,Luca Di Tommaso

doi:10.1038/s42003-021-02595-z

Abstract

Luminal-like breast cancer (BC) constitutes the majority of BC subtypes, but, differently from highly aggressive triple negative BC, is poorly infiltrated by the immune system. The quality of the immune infiltrate in luminal-like BCs has been poorly studied, thereby limiting further investigation of immunotherapeutic strategies. By using high-dimensional single-cell technologies, we identify heterogeneous behavior within the tissue-resident memory CD8+ T (Trm) cells infiltrating luminal-like tumors. A subset of CD127− CD39hi Trm cells, preferentially present in the tumor compared to the adjacent normal breast tissue or peripheral blood, retains enhanced degranulation capacity compared to the CD127+ CD39lo Trm counterpart ex vivo, and is specifically associated with positive prognosis. Nevertheless, such prognostic benefit is lost in the presence of highly-suppressive CCR8hi ICOShi IRF4+ effector Tregs. Thus, combinatorial strategies aiming at boosting Trm function and infiltration while relieving from Treg-mediated immunosuppression should be investigated to achieve proper tumor control in luminal-like BCs.

Highlights

Luminal-like breast cancer (BC) constitutes the majority of BC subtypes, but, differently from highly aggressive triple negative BC, is poorly infiltrated by the immune system
Reanalysis of 3637 T cells sorted in silico from eight patients on the basis of CD3E expression identified five and six clusters of CD4+ and CD8+ T cells, respectively (Fig. 1a)
As far as CD8+ T cells were concerned, we revealed an abundant cluster of memory T cells, C1, overexpressing IL7R, KLRC1, and KLRB1, two clusters of cytotoxic/effector-like CD8+ T cells overexpressing GZMK and GZMA (C0) or GZMB, GZMH, GNLY, and PRF1 (C3), and a tissue-resident memory (Trm) cluster, C4, overexpressing ITGAE and CD69 (Fig. 1a, CD8)

Summary

Introduction

Luminal-like breast cancer (BC) constitutes the majority of BC subtypes, but, differently from highly aggressive triple negative BC, is poorly infiltrated by the immune system. A subset of CD127− CD39hi Trm cells, preferentially present in the tumor compared to the adjacent normal breast tissue or peripheral blood, retains enhanced degranulation capacity compared to the CD127+ CD39lo Trm counterpart ex vivo, and is associated with positive prognosis. Such prognostic benefit is lost in the presence of highly-suppressive CCR8hi ICOShi IRF4+ effector Tregs. Combinatorial strategies aiming at boosting Trm function and infiltration while relieving from Treg-mediated immunosuppression should be investigated to achieve proper tumor control in luminal-like BCs. 1234567890():,; The interplay between the immune system and cancer cells has been recognized as a hallmark of cancer, involved in its pathogenesis, growth, and resistance to medical treatments[1].

Methods

Results

Conclusion