Cancer is often regarded as an inflammatory disease. This means that, our immune system usually reacts to the presence of cancer cells and eliminates them by recruiting the heavy immune weaponry, such as cytotoxic lymphocytes or natural killer cells, to the tumor site. Cancers grow when their cells gain the ability to hide from the immune system.

Cytokines are the signals by which immune cells orchestrate their response. The initial signals are sent out by macrophages, the tissue-resident immune cells and first line of defense and, among those, two cytokines stand out: the Tumor Necrosis Factor alpha (TNFa) and the gamma Interferon. Beyond recruiting other immune cells, cytokines also act on cancer cells, inducing growth arrest, senescence and death. Thus, it is critical to understand what defines the response of cancer cells to cytokines.

Both TNFa and interferon penetrate the cancer cell and activate a series of genetic programs encoded in their DNA. To do so, they must access the information encoded in DNA. However, this molecule is so large that needs to be compacted into the cell’s nucleus and this is done by a family of proteins called histones that wrap up the DNA into small bundles called nucleosomes. Highly compacted DNA is unreadable for the cell, so histones also limit the accessibility to genetic information, being one of the most heavily used gene regulation systems in eukaryotes.

The researchers’ team, spearheaded by Dr. David Corujo and led by Dr. Marcus Buschbeck (Josep Carreras Leukaemia Research Institute) and Dr. Carolina Armengol (Germans Trias i Pujol Research Institute - IGTP) found that a group of histones called macroH2A, and its different variants, impose restrictions to the effects of the cytokines. In this regard, they found that macroH2As act by altering the contacts of gene regulatory regions, the promoters, with its distant activators upon the DNA, the so-called enhancers. Such contacts are highly dependent on the 3D positioning of chromatin in the nucleus.

In addition, the published results, extending on previous findings of the same group, show that macroH2A variants control genes involved in the cell’s secretion of signaling molecules in response to cytokines. These signaling molecules are responsible of the overall tissue response to the immune system, for instance by helping activate the incoming lymphocytes, and can affect the neighbor cells as well as the secreting cell itself. When this system is altered, it may end up in a situation where a tumor not just fails to activate the immune cells, but actively hinders its activation by other means, in a coordinated manner.

The research from the Buschbeck’s and Armengol’s lab provides new knowledge on the impact of histone variants on how cancer cells interact with the immune system. Basic research studies like this one provide fundamental insight that will hopefully help us to use the patient’s own immune system to combat this dreadful disease in the future.

Reference article:

“MacroH2As regulate enhancer-promoter contacts affecting enhancer activity and sensitivity to inflammatory cytokines”

David Corujo, Roberto Malinverni, Juan Carrillo-Reixach, Oliver Meers, Arce Garcia-Jaraquemada, Marguerite-Marie Le Pannérer, Vanesa Valero, Ainhoa Pérez, Álvaro del Río Álvarez, Laura Royo, Beatriz Pérez-González, Helena Raurell, Rafael D Acemel, José M Santos-Pereira, Marta Garrido, José Luís Gómez-Skarmeta, Lorenzo Pasquali, Josep Manyé, Carolina Armengol, Marcus Buschbeck.

Cell Reports Vol.39 (12), June 21, 2022. https://doi.org/10.1016/j.celrep.2022.110988