Senescent cells as a vaccine against cancer?

Cancer cells have a series of characteristics that allow the immune system to identify and attack them. However, the same cells create an environment that blocks immune cells and protects the tumor. Thus, the immune cells cannot access the cancer cells and cannot eliminate them. The scientific community has been working for years to increase the effectiveness of the immune system by exposing it to dead tumor cells.

Scientists at the Barcelona Institute for Research in Biomedicine (IRB Barcelona), led by ICREA researcher Dr. Manuel Serrano and Dr. Federico Pietrocola, now at the Karolinska Institute in Sweden, have investigated how inducing senescence in cancer cells improves the effectiveness of the antitumor immune response, to a greater degree than the dead cells that are used on a regular basis. The researchers have vaccinated healthy mice with senescent cancer cells, subsequently induced the formation of tumors and have observed that the animals do not develop cancer or the number of mice that develop it is very significantly reduced. They have also analyzed the efficacy of vaccination on animals with already developed tumors and, although the results are more moderate, due to the protective barrier of the tumor, improvements are also observed.

“Our results indicate that senescent cells are a preferred option when it comes to stimulating the immune system against cancer, and open the way to consider vaccination with these cells as a possible therapy,” explains Dr. Serrano, head of the Plasticity laboratory Cell and Disease at IRB Barcelona.

The researchers have tested the technique in study models of melanoma, a type of cancer that is characterized by high activation of the immune system, and also in pancreatic cancer models that, a priori, have very little immunogenic activity. Prophylactic therapy is effective in both cases. They have also complemented the study with samples of tumors from cancer patients and have confirmed that they also have a greater ability to activate the immune system.

The group is now studying the effect of adding vaccination with senescent cells and immunotherapy treatments, to study the combined efficacy of both therapies against cancer.

Immune cell infiltrate (in deep red) around senescent cancer cells (large nuclei marked in blue). (Image: IRB Barcelona. CC BY-NC-ND)

Senescence and its potential to activate the immune system

Senescence is a state of latency reached by damaged or aged cells, in which they do not reproduce but do not disappear either. Senescent cells emit information signals to their environment, which warn of their presence and thus favor the inflammatory response and tissue regeneration.

In the context of cancer, researchers led by Dr. Serrano have discovered that senescent cells, due to their characteristics, are a good option to stimulate the immune system and improve its response to the tumor. On the one hand, because being living cells, they remain in the body longer than dead cells, stimulating the immune system for a longer period of time. On the other hand, being cells that do not divide, they do not have the capacity to regenerate the tumor.

“Our study concludes that the induction of senescence in tumor cells improves, on the one hand, the recognition of tumor cells by the immune system and, on the other, increases the intensity of the response they generate, so these are very positive”, explains Inés Marín, doctoral student from the same laboratory and first author of the study.

As observed in this study, senescent cells present unique signals, which promote recognition by the immune system and its activation, and which differ from those presented by cells before senescence has been induced.

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

The discovery by the Cellular Plasticity and Disease laboratory has been published simultaneously and in the same academic journal as another study, carried out at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York and completed in collaboration with IRB Barcelona. This other work, signed by Dr. Direna Alonso-Curbelo, now head of the Inflammation, Tissue Plasticity and Cancer laboratory at IRB Barcelona, ​​and Dr. Scott W. Lowe, reaches complementary conclusions, despite studying the subject from a very different approach.

Specifically, the work has focused on characterizing how the induction of senescence in tumor cells alters the communication between the tumor and the immune system. “Until now, 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, discovering that senescence increases the ability of cells to “receive” signals from their environment that activate key pathways for their recognition and destruction by cytotoxic T cells” explains Dr. Alonso-Curbelo.

This work demonstrates that this ability to “receive” signals from the environment, increased by senescence induction, amplifies signals such as interferon, making tumor cells more visible to the immune system and increasing their antitumor potential in liver cancer models.

Other diseases related to aging and in which there is a prevalent presence of senescent cells, such as atherosclerosis, could also benefit from possible vaccines with senescent cells. In this sense, the IRB Barcelona scientists also detail that senescent cells can be mistakenly recognized by immune cells as if they were foreign cells. These findings are in line with work published by other researchers on cells subjected to stress, which can also be mistaken for foreign cells.

The study led by IRB Barcelona has been carried out in collaboration with the laboratories of Dr. María Abad and Dr. Alena Gros of the Valle de Hebrón Institute of Oncology (VHIO) in Barcelona, ​​who have complemented the study with samples of tumors from cancer patients and have confirmed that they also have a greater ability to activate the immune system. The laboratory of Dr. Etienne Caron of the Sainte-Justine University Hospital Research Center in Canada and the technological platforms of Biostatistics and Bioinformatics in charge of Dr. Camille Stephan-Otto Attolini and of Histopathology, directed by Dr. Neus, have also collaborated. Prats, both at IRB Barcelona.

The study carried out by Inés Marín’s team is entitled “Cellular senescence is immunogenic and promotes anti-tumor immunity”. And it has been published in the academic journal Cancer Discovery. (Source: IRB Barcelona)