Cancer treatments, including chemotherapy, in addition to killing large numbers of tumor cells, also cause the generation of senescent tumor cells (also called “zombie cells”). Although senescent cells do not reproduce, they unfortunately generate a favorable environment for the expansion of tumor cells that may have escaped the effects of chemotherapy and ultimately cause the tumor to grow back.
An international team of researchers led by Dr. Manuel Serrano from IRB Barcelona has described how tumor cells that have become senescent after chemotherapy activate the PD-L2 protein to protect themselves from the immune system by recruiting immunosuppressive cells. The latter creates an inhibitory environment that impairs the ability of lymphocytes to kill tumor cells.
The results of research were published in Nature Cancer
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Based on these findings, scientists wondered what the effect of inactivating PD-L2 would be. Interestingly, senescent cells lacking PD-L2 are rapidly eliminated by the immune system. This intercepts the ability of senescent cells to create an immunosuppressive environment and, as a result, lymphocytes retain their full ability to kill those tumor cells that may have escaped the effects of chemotherapy.
“By blocking PD-L2 in mouse models, we saw that chemotherapy is more effective against cancer. This discovery paves the way for considering the use of a potential PD-L2 inhibitor as an adjuvant in the treatment of this disease,” explains Dr. Manuel Serrano, currently at Altos Labs (Cambridge, UK).
The study was conducted using cell lines and animal models of melanoma, pancreatic and breast cancer.
Cellular senescence is a process that occurs naturally during aging and is common in the context of cancer therapies. Most of these treatments (such as chemotherapy and radiotherapy) work by causing extensive cellular damage and, consequently, lead to the formation of senescent cells, particularly within the tumor. The team of scientists will now study whether senescent cells linked to the aging of the organism also have high levels of PD-L2.
“Although further experiments are needed to characterize the role of this molecule in different types of human cancer, this work has improved our understanding of the role of PD-L2 and the interaction of senescent cells with the immune system,” explains Dr. José Alberto López, postdoctoral researcher from the same laboratory and first author of the work together with Dr. Selim Chaib.
In 2024, Dr. López will start a new laboratory at the Salamanca Cancer Research Center, a joint effort between the University of Salamanca and CSIC. Dr. Chaib is now at the Mayo Clinic, Minnesota (United States).
This work was carried out in collaboration with groups led by Drs. Joaquín Arribas, Alena Gros and María Abad of the Vall d'Hebron Institute of Oncology (VHIO). Dr. Arribas is now the director of the Hospital del Mar Research Institute (IMIM) and Dr. Abad works at Altos Labs.
The team led by Drs. James Kirkland and Tamara Tchkonia from the Mayo Clinic contributed important data to this study. This work also involved the company Rejuveron Senescent Therapeutics, which is developing antibodies against PD-L2 for clinical use and has headquarters in Zurich and Barcelona.
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