Chemotherapy is more effective when using immunotherapy for senescent cells.

treat cancer or chemotherapy or other targeted therapies, in addition to killing a large number of tumor cells, lead to the formation of senescent tumor cells. These cells, also called zombies, do not reproduce, but unfortunately they create a favorable environment for the tumor to grow again.

Researchers from IRB Barcelona led by Manuel Serranodescribed how cancer cells that become senescent after treatment activate the PD-L2 protein to protect themselves from the immune system while recruiting immunosuppressive cells.

These suppressor cells create an inhibitory environment that prevents lymphocytes from accessing and acting against cancer cells. Thus, senescent cells promote tumor growth and limit the effectiveness of chemotherapy.

By blocking PD-L2, we saw in mouse models that chemotherapy was more effective against cancer.

Manuel Serrano
— Main author

“By blocking PD-L2, we saw in mouse models that chemotherapy was more effective against cancer. This opens the door to considering the use of a potential PD-L2 inhibitor as an adjuvant in the treatment of this disease,” explains Serrano, currently a research scientist at Altos Labs (Cambridge, UK).

Research published in the journal Nature Cancerwas conducted using cell lines and animal models to study skin, pancreatic, and breast cancers.

Common phenomenon in cancer therapy

Cellular senescence is a process that occurs naturally with aging and has become commonplace in the context of cancer treatment. Most of them (such as chemotherapy or radiation therapy) act by causing multiple cellular damage and, as a consequence, lead to the formation of senescent cells, especially within the tumor.

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.

Jose Alberto Lopez
— First author of the study

The 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,” he concludes. Jose Alberto Lopezthe first author of the work.

This work has received funding from the Spanish Association Against Cancer, La Caixa Foundation, BBVA Foundation, Ministry of Science and Innovation, Department of Research and Universities of the Generalitat of Catalonia, European Research Council (ERC) and European FEDER Funds.

Link: Selim Chaib, Jose Alberto Lopez and others – “The effectiveness of chemotherapy is limited by intratumoral senescent cells expressing PD-L2.” Magazine Nature Cancer, 2024 | DOI: 10.1101/2022.11.04.501681.