Vaccination with senescent cells could be a possible therapy against cancer

Vaccination with senescent cells could be a possible therapy against cancer

Cancer cells have a number of characteristics that allow the immune system to recognize and attack them. However, these same cells create an environment that blocks immune cells and protects the tumor. This means immune cells cannot reach the cancer cells to remove them. Science has been working for years to increase the effectiveness of the immune system against cancer by using vaccines based on dead tumor cells.

IRB Barcelona scientists led by ICREA researcher Dr. Manuel Serrano and Dr. Federico Pietrocola, now at Karolinska Institutet in Sweden, have studied how inducing senescence in cancer cells improves the effectiveness of the immune response to a greater extent than dead cancer cells. After vaccinating healthy mice with senescent cancer cells and then stimulating tumor formation, the researchers observed that the animals developed no cancer or significantly less cancer. They also analyzed the effectiveness of the vaccination in animals that had already developed tumors. Although results were more moderate due to the tumor's protective barrier, improvements were also observed in this setting.

Our results show that senescent cells are a preferred option when it comes to stimulating the immune system against cancer and pave the way to consider vaccination with these cells as a possible therapy.”

Dr. Manuel Serrano, head of the Laboratory of Cellular Plasticity and Diseases at IRB Barcelona

The researchers tested the technique in animal models of melanoma, a type of cancer characterized by strong activation of the immune system, as well as pancreatic cancer models, which present strong barriers to immune cells. Prophylactic vaccination therapy with senescent cancer cells was effective against both tumor types. They also supplemented the study with tumor samples from cancer patients, confirming that human cancer cells also have a greater ability to activate the immune system if they have been previously aged.

The group is now studying the combined effectiveness of senescent cell vaccination and immunotherapy treatments.

Senescence and its ability to activate the immune system

Senescence is a latent state that damaged or aged cells reach in which they do not multiply but do not disappear either. Senescent cells release information signals to their environment that warn of their presence and stimulate an inflammatory response and tissue regeneration.

In connection with cancer, researchers led by Dr. Serrano discovers that their properties make senescent cells a good option to activate the immune system and improve its response to the tumor. On the one hand, senescent cells, as living cells, remain in the body longer than dead ones and can therefore stimulate the immune system for longer. On the other hand, since these cells do not divide, they cannot regenerate the tumor.

"Our study concludes that the induction of senescence in tumor cells improves the recognition of these cells by the immune system and also increases the intensity of the response they generate. So our results are very positive," explains Inés Marín, doctoral student from the same laboratory and first author of the study.

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As observed in this study, senescent cells present unique signals that stimulate recognition by and activation of the immune system and that are distinct from those presented by cells before senescence was induced.

A parallel discovery by Dr. Scott W. Lowe and Dr. Direna Alonso-Curbelo

The Cellular Plasticity and Disease Laboratory's discovery was published simultaneously and in the same journal as another paper led by Memorial Sloan Kettering Cancer Center (MSKCC) in New York and completed in collaboration with IRB Barcelona. The latter, by Dr. Direna Alonso-Curbello, now head of the Inflammation, Tissue Plasticity and Cancer Laboratory at IRB Barcelona, ​​​​and Dr. Authored by Scott W. Lowe, it comes to complementary conclusions, although it examines the topic with a very different approach.

In short, the work begun at MSKCC focused on describing how induction of senescence in tumor cells alters the molecular programs that mediate communication between the tumor and the immune system. “To date, most studies have focused on the ability of senescent cells to “send” inflammatory signals to their environment. Our work shows that this communication is bidirectional, demonstrating that senescence increases the ability of cells to “receive” signals from their environment. “Activate key pathways for their recognition and destruction by cytotoxic T cells,” explains Dr. Alonso-Curbelo.

This work shows that the ability to “receive” signals from the environment, increased by the induction of senescence, enhances the anti-tumor effect of signals such as interferon, makes tumor cells more visible to the immune system, and reactivates anti-tumor immunity in liver cancer models.

Other age-related diseases and those in which senescent cells predominate, such as atherosclerosis, could also benefit from potential senescent cell vaccines. In this context, the scientists at IRB Barcelona also report that senescent cells can be incorrectly recognized by immune cells as foreign cells. These results are consistent with those of other researchers working on cells exposed to stress, which can also be mistaken for foreign cells.

The study, led by the IRB Barcelona, ​​was carried out in collaboration with the laboratories led by Dr. Maria Abad and Dr. Alena Gros at the Vall d’Hebron Institute of Oncology (VHIO) in Barcelona and Dr. Etienne Caron conducted at the CHU Sainte-Justine Research Center in Canada. In addition, the Department of Biostatistics and Bioinformatics under the direction of Dr. Camille Stephan-Otto Attolini and the central facility for histopathology under the direction of Dr. Neus Prats, both at IRB Barcelona.

Source:

Institute for Biomedical Research – IRB

Reference:

Marin, M., et al. (2022) Cellular senescence is immunogenic and promotes anti-tumor immunity. Cancer discovery. doi.org/10.1158/2159-8290.CD-22-0523.

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