Teams from UNIGE, Massachusetts General Hospital and the University of Munich unveil a major mechanism that protects immune cells mobilized against tumors.
Most cancer immunotherapies rely on the ability of cytotoxic T lymphocytes (CTL), key cells of the immune system, to recognize and destroy cancer cells. However, tumors are a hostile environment for CTLs, which can eliminate them before they can trigger their anti-tumor activity. An international team has succeeded in deciphering the strategies used by CTLs to survive and carry out their task. These lymphocytes find refuge in niches in the tumor tissue, where they receive survival factors. This work, published in the journal Cell, will allow the development of even more effective immunotherapies so that the immune system can defeat aggressive cancers.
Activated in the lymph nodes, CTLs then move into the bloodstream to reach tumors through the bloodstream. However, tumors are an inhospitable environment for CTLs, which limits their ability to survive there. “Are there protective mechanisms for CTLs and could they be exploited to increase the effectiveness of immunotherapies? This is what we wanted to know,” says Mikaël Pittet, ISREC Foundation Chair in Immuno-Oncology at the Department of Pathology and Immunology and the Centre for Translational Research in Onco-Hematology at the UNIGE Faculty of Medicine, a member of the Ludwig Institute for Cancer Research, and a member of the Swiss Cancer Centre Léman, who participated in this work.
A specific survival niche
The team discovered that in order to survive in tumors, T cells must spend time in specific survival niches that form directly next to certain blood vessels in the tumor stroma, the tissue surrounding the cancer cells. Once in the niches, CTLs can interact with other immune cells, in particular a population of dendritic cells called DC3, recently identified by Mikaël Pittet and colleagues. “These DC3 dendritic cells produce certain proteins, such as the cytokine IL-15, that allow CTLs to survive long enough in tumors and are thus much more effective in eliminating cancer cells,” explains Thorsten Mempel, associate director of the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital and professor of medicine at Harvard Medical School, who led this work.
Identification of a protective chemokine
But how do CTLs make their way into these survival niches and stay there long enough? The scientists turned their attention to chemokines, chemotactic guidance factors that direct the migration of immune cells and help them “sense” and find their way into tissue. “It turns out that a chemokine, called CXCL16, is highly expressed by DC3 dendritic cells located in protective niches; the CXCR6 receptor, which specifically recognizes CXCL16, is expressed by some CTLs. Thus, DC3 cells are able to indicate their position to CTLs and then, once recruited, to provide them with survival signals for tumor elimination,” explains Mikäel Pittet.
The identification of these immune mechanisms could allow the development of more effective immunotherapies. For example, one of the research groups involved in this study has already modified CTLs to express more CXCR6. This change increases the ability of the cells to control tumor growth in animal models of cancer, validating this finding.
References: https://doi.org/10.1016/j.cell.2021.07.015, see also: https://doi.org/10.1016/j.ccell.2021.08.010
