Killing zombie cells makes chemotherapy more effective

The goal of cancer therapy is to destroy as many cancer cells as possible without damaging healthy tissue. However, some malignant cells do not disappear, but become so-called senescent or zombie tumor cells which, although they do not multiply, suppress the body’s defenses and create a favorable environment for tumor regrowth.

A study carried out by scientists from IRB Barcelona led by Dr. Manuel Serrano, showed how cancer cells that become senescent after treatment activate the PD-L2 protein to protect themselves from the immune system while recruiting immune suppressor cells that create an inhibitory environment that prevents lymphocytes from accessing and fighting the cancer cells . Thus, senescent cells promote tumor growth and limit the effectiveness of chemotherapy.

“Blocking PD-L2 In mouse models, we saw that chemotherapy was more effective against cancer. This opens the way to considering the use of a potential PD-L2 inhibitor as an adjuvant in the treatment of this disease,” explains Dr. Manuel Serrano, currently a research scientist at Altos Labs (Cambridge, UK). The study was conducted on cell lines and animal models of skin, pancreatic and breast cancer, and the results were published in a journal. Nature Cancer.

Control cellular aging to better fight cancer

Cellular senescence is a process that occurs naturally with aging and has become commonplace in the context of cancer treatment. Most cancer treatments (such as chemotherapy or radiation therapy) cause multiple cell damage and, as a result, cause cellular aging, especially within the tumor.

In a laboratory set up by researcher Manuel Serrano at IRB Barcelona, ​​they successfully demonstrated that new immunotherapytested on animal models, eliminates senescent cells and increases the effectiveness of chemotherapy

. To do this, the researchers activated the defense using a hitherto overlooked pathway: the PDL2 protein. Senescent cells have a membrane that suppresses the immune system. Solution: “edit the PDL2 protein.” Thus, “the immune system can destroy both senescent and tumor cells, since the former protects the latter,” explained Dr. José Alberto López, a postdoctoral fellow in the same lab and first author of the paper with Dr. Selim Chaib.

Researchers have successfully shown that a new therapy in animals eliminates senescent cells and improves the effectiveness of chemotherapy.

The scientific team will now study whether aging associated with aging of the body correlates with increased levels of PD-L2. “Although more experiments are needed to characterize the role of this molecule in various human tumors, this work has allowed us to expand our knowledge of the role of PD-L2 and the interaction of senescent cells with the immune system,” concludes Dr. Lopez. . .

This work was carried out in collaboration with the groups of Dr. Joaquín Arribas, Dr. Alena Gros and Dr. Maria Abad at the Vall d’Hebron Institute of Oncology (VHIO). Dr. Arribas also heads the Hospital del Mar Research Institute (IMIM), and Dr. Abad works at Altos Labs. A team led by Dr. James Kirkland and Dr. Tamara Chkonia from the Mayo Clinic provided critical data for this study. Rejuveron Senescent Therapeutics, a company with offices in Zurich and Barcelona, ​​involved in the clinical development of antibodies against PD-L2, also took part in the work.

Fountain: IRB Barcelona