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January 25, 2024 — A groundbreaking study led by Dr. Manuel Serrano at IRB Barcelona sheds light on a previously overlooked aspect of cancer therapy — the role of senescent tumor cells, often referred to as “zombie cells,” in impeding the effectiveness of chemotherapy. The international research team discovered that senescent cancer cells activated the PD-L2 protein post-chemotherapy, creating an immunosuppressive shield against the body’s immune system.
Senescent cells, a natural occurrence during aging and a common outcome of cancer therapies like chemotherapy and radiotherapy, do not proliferate but contribute to the regeneration of tumors. In response to chemotherapy, these senescent cells activate PD-L2, protecting themselves from the immune system and recruiting immune suppressor cells, establishing an inhibitory environment that hinders the ability of lymphocytes to eliminate cancer cells.
The researchers explored the effects of inactivating PD-L2, leading to a surprising outcome. Senescent cells lacking PD-L2 were rapidly eliminated by the immune system, preventing the creation of an immunosuppressive environment. Consequently, lymphocytes retained their full capacity to target and eliminate cancer cells that may have survived the initial effects of chemotherapy.
Dr. Manuel Serrano, currently affiliated with Altos Labs in Cambridge, United Kingdom, expressed optimism about the findings, stating, “By blocking PD-L2 in mouse models, we have seen that chemotherapy is more effective against cancer. This finding paves the way to consider the use of a potential PD-L2 inhibitor as an adjuvant in the treatment of this disease.”
The study, conducted using cell lines and animal models of melanoma, pancreatic, and breast cancer, provides valuable insights into the intricate relationship between senescent cells and the immune system. Researchers are now exploring whether senescent cells associated with the natural aging process also exhibit elevated levels of PD-L2.
Dr. Jose Alberto Lopez, the first author of the study, emphasized the need for further experiments to characterize the role of PD-L2 in different types of human cancers. The collaborative effort involved researchers from the Vall d’Hebron Institute of Oncology, the Mayo Clinic, and Rejuveron Senescence Therapeutics, a company developing antibodies against PD-L2 for clinical use.
The breakthrough discovery opens new avenues for enhancing cancer treatment efficacy by targeting senescent cells and their interaction with the immune system. The study’s implications could potentially revolutionize cancer therapy and contribute to more effective and targeted treatments in the future.
