CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer

Paulino Tallón De Lara,Karina Silina,Sònia Tugues,Marijne Vermeer,Stefanie Hiltbrunner,Joaquín Urdinez,Nicolás Núñez,Isabelle Glarner,Hideo Yagita,Bettina Sobottka,Burkhard Becher,Maries Van Den Broek,Holger Moch,Farkhondeh Movahedian Attar,Héctor Castañón,Virginia Cecconi

doi:10.1038/s41467-021-21045-2

Abstract

Some breast tumors metastasize aggressively whereas others remain dormant for years. The mechanism governing metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identify a discrete population of CD39+PD-1+CD8+ T cells in primary tumors and in dormant metastasis, which is hardly found in aggressively metastasizing tumors. Using blocking antibodies, we find that dormancy depends on TNFα and IFNγ. Immunotherapy reduces the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39+PD-1+CD8+ T cells prevents metastatic outgrowth. In human breast cancer, the frequency of CD39+PD-1+CD8+ but not total CD8+ T cells correlates with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+PD-1+CD8+ T cells for controlling experimental and human breast cancer. Thus, we suggest that a primary breast tumor could prime a systemic, CD39+PD-1+CD8+ T cell response that favors metastatic dormancy in the lungs.

Highlights

The mechanism governing metastatic dormancy remains largely unknown
Infiltration of the primary tumor by T cells was shown to correlate with a good prognosis[18], it remains unclear whether this correlation is explained by cytotoxic T cells that eliminate cancer cells or by T cells that prevent the outgrowth of cancer cells and induce dormancy[19,20]
Despite absence of macro-metastasis, we found disseminated 4T07 cells in the lungs (Supplementary Fig. 1e) of all mice, suggesting that 4T07 disseminated cancer cells (DCCs) seed the lungs but fail to grow out

Summary

Introduction

The mechanism governing metastatic dormancy remains largely unknown. Through highparametric single-cell mapping in mice, we identify a discrete population of CD39+PD-1+ CD8+ T cells in primary tumors and in dormant metastasis, which is hardly found in aggressively metastasizing tumors. ~20% of disease-free patients will relapse within 7 years after resection, and patients that appear to be cured from breast cancer have a higher mortality than the rest of the population even 20 years after surgery[4,5] Such late relapses are thought to result from disseminated cancer cells (DCCs) that reached different organs but remained dormant for several years[6]. We sought to understand the mechanism that governs metastatic dormancy of DCCs and discovered that the primary tumor primes a systemic, CD8+ T cell response that prevents metastatic outgrowth of DCCs in the lungs. The protective T cells expressed markers that are generally associated with activation and exhaustion Promoting such a response may provide a rationale for the development of future immunotherapies that aim to prevent metastatic relapse

Methods

Results

Conclusion