Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche

Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxiainduced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.

Automated summary

This study discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent and form clusters with reduced immune infiltration. These quiescent cancer cells show superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. Single-cell RNA sequencing revealed differential phenotypes in infiltrating cells based on their intra-tumor location, and uncovered hypoxia-induced immune-suppressive programs. The findings suggest that eliminating quiescent cancer cells holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.