AI Article Synopsis
- - Breast cancer cells can survive chemotherapy by entering a state of senescence, which helps them evade various forms of cell death and escape immune detection.
- - Researchers identified two distinct populations of tumor cells in residual disease: one responsive to interferon and the other regulated by p53 signaling, both of which contribute to immune evasion.
- - Combining chemotherapy with treatments targeting immune checkpoints (like PD-L1 and CD80) increased T cell presence but still failed to fully eliminate tumors, indicating the need for more effective immune targeting approaches.
Article Abstract
Breast cancer cells must avoid intrinsic and extrinsic cell death to relapse following chemotherapy. Entering senescence enables survival from mitotic catastrophe, apoptosis and nutrient deprivation, but mechanisms of immune evasion are poorly understood. Here we show that breast tumors surviving chemotherapy activate complex programs of immune modulation. Characterization of residual disease revealed distinct tumor cell populations. The first population was characterized by interferon response genes, typified by Cd274, whose expression required chemotherapy to enhance chromatin accessibility, enabling recruitment of IRF1 transcription factor. A second population was characterized by p53 signaling, typified by CD80 expression. Treating mammary tumors with chemotherapy followed by targeting the PD-L1 and/or CD80 axes resulted in marked accumulation of T cells and improved response; however, even combination strategies failed to fully eradicate tumors in the majority of cases. Our findings reveal the challenge of eliminating residual disease populated by senescent cells expressing redundant immune inhibitory pathways and highlight the need for rational immune targeting strategies.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9923777 | PMC |
| http://dx.doi.org/10.1038/s43018-022-00466-y | DOI Listing |
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