Could senescence phenotypes strike the balance to promote tumor dormancy?

After treatment and surgery, patient tumors can initially respond followed by a rapid relapse, or respond well and seemingly be cured, but then recur years or decades later. The state of surviving cancer cells during the long, undetected period is termed dormancy. By definition, the dormant tumor cells do not proliferate to create a mass that is detectable or symptomatic, but also never die. An intrinsic state and microenvironment that are inhospitable to the tumor would bias toward cell death and complete eradication, while conditions that favor the tumor would enable growth and relapse. In neither case would clinical dormancy be observed. Normal cells and tumor cells can enter a state of cellular senescence after stress such as that caused by cancer therapy. Senescence is characterized by a stable cell cycle arrest mediated by chromatin modifications that cause gene expression changes and a secretory phenotype involving many cytokines and chemokines. Senescent cell phenotypes have been shown to be both tumor promoting and tumor suppressive. The balance of these opposing forces presents an attractive model to explain tumor dormancy: phenotypes of stable arrest and immune suppression could promote survival, while reversible epigenetic programs combined with cytokines and growth factors that promote angiogenesis, survival, and proliferation could initiate the emergence from dormancy. In this review, we examine the phenotypes that have been characterized in different normal and cancer cells made senescent by various stresses and how these might explain the characteristics of tumor dormancy.

Breast cancer cells survive chemotherapy by activating targetable immune-modulatory programs characterized by PD-L1 or CD80.

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.