Clusters of quiescent cancer cells drive resistance to immunotherapy in TNBC

Researchers led by Ludwig Harvard’s Judith Agudo reported in an April paper in Cell that quiescent cancer cells congregate in clusters in primary tumors of triple-negative breast cancer (TNBC) and that these clusters play a central role in resistance to immunotherapy. The clusters, which express genes associated with chemotherapy resistance and metastatic capability, form a niche within the tumor microenvironment that is poorly infiltrated with immune cells and markedly starved of oxygen. An integrated spatial and single-cell gene expression analysis of this niche revealed the extensive activation of gene expression programs associated with hypoxia—regulated by the transcription factor HIF1a—in the cancer cells. The clusters are also infiltrated with tumor-supporting fibroblasts and dysfunctional dendritic cells, immune cells that ordinarily help orchestrate anti-tumor immune responses. The activation of hypoxic gene expression programs in cancer cells, Judith and her colleagues found, also promotes the terminal exhaustion of T cells and suppresses their killing of cancer cells. Judith and her colleagues propose that quiescent cancer cell clusters form reservoirs of immunotherapy-resistant cancer cells, and that their targeted disruption could improve immunotherapy against TNBC and thwart disease recurrence.

Read the study: Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche, Cell, 2022 April 20 Epub

This article appeared in the September 2022 issue of Ludwig Link. Click here to download a PDF (1 MB)


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