As tumors develop, they evolve genetically. How does the immune system act when faced with tumor cells? How does it exert pressure on the genetic diversity of cancer cells? Scientists from the Institut Pasteur and Inserm used in vivo video techniques and cell-specific staining to visualize the action of immune cells in response to the proliferation of cancer cells. The findings have been published in the journal Science Immunology on November 23, 2018.
Over time, the uncontrolled proliferation of tumor cells results in the accumulation of new mutations and changes to their genome. This gradual process creates significant genetic diversity among the cancer cells in any given patient. And although the cells in the immune system, especially T cells, are potentially able to eliminate these abnormal cells, tumor diversity can have a harmful effect, complicating the action of the immune system and rendering some therapies ineffective. Understanding this frantic race between tumor development and the immune response is key to the success of future immunotherapy techniques.
Scientists in the Dynamics of Immune Responses Unit (Institut Pasteur/Inserm), directed by Philippe Bousso, in collaboration with Ludovic Deriano, Head of the Genome Integrity, Immunity and Cancer Unit (Institut Pasteur), investigated how spontaneous immune responses to tumors influence this tumor heterogeneity. They demonstrated that the immune system can employ mechanisms to significantly reduce tumor diversity, favoring the emergence of more genetically homogeneous tumor cells.
In their study, the scientists marked each cancer cell subclone with a separate color in a mouse model. By monitoring these different colors they were therefore able to characterize the evolution of tumor heterogeneity in time and space. They were also able to observe the contacts between T cells and cancer cells and determine how some tumor cells are destroyed. Their research highlights the drastic impact the immune system can have on tumors by reducing their heterogeneity.
Visualizing the action of stained immune cells.
In this video, the tumor cells are shown in gray. The tumor-specific T-cells, in purple, come into contact with the cancer cells and destroy them. The killed cells are shown in blue. In green, the control cells circulate but do not kill the tumor cells. © Institut Pasteur / Philippe Bousso
Visualizing different clusters of cancer cell clones.
This video illustrates how tumor subclones, each marked by a different color (blue, orange and green), develop in the bone marrow. The vessels are shown in white. © Institut Pasteur / Philippe Bousso
The same impact on the heterogeneity of tumor cells has also been observed in response to immunotherapies that release the brakes on the immune system, an approach which was awarded the Nobel Prize in Physiology or Medicine this year.
This research shows that taking into account the interaction between immunotherapies and tumor heterogeneity could contribute to the development of optimum therapeutic combinations and sequences.
In addition to the organizations mentioned above, this research was funded by the Fondation de France, the French National Cancer Institute (INCa) and the European Research Council (ERC).
The Immune System Profoundly Restricts Intratumor Genetic Heterogeneity, Science Immunology, November 23, 2018
Idan Milo (1,2), Marie Bedora-Faure (3), Zacarias Garcia (1,2), Ronan Thibaut (1,2,4), Leïla Périé (5,6), Guy Shakhar (7), Ludovic Deriano (3) and Philippe Bousso (1,2)
(1) Dynamics of Immune Responses Unit, Equipe Labellisée Ligue Contre le Cancer, Institut
Pasteur, 75015 Paris, France.
(2) INSERM U1223, 75015 Paris, France.
(3) Genome Integrity, Immunity and Cancer Unit, Department of Immunology, Department of
Genomes and Genetics, Institut Pasteur, 75015 Paris, France.
(4) University Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, rue du Dr Roux, 75015 Paris,
(5) Institut Curie, PSL Research University, CNRS UMR168, 11 rue Pierre et Marie Curie, 75005 Paris, France.
(6) Sorbonne Universités, UPMC University Paris 06, 4 place Jussieu, 75005 Paris, France
(7) Department of Immunology, the Weizmann Institute of Science, Rehovot 76100, Israel.