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A research study on cancer led by Ludwig has deciphered a complex molecular conversation between cancer and immune cells, essential to orchestrate the successful invasion of tumors by T cells that destroy cancer cells.
We show that two key chemokines, CCL5 and CXCL9, are universally involved in T cell infiltration in all solid tumors. Their simultaneous presence in tumors is an essential condition for T-cell engraftment and the establishment of an inflamed tumor, also known as a "hot tumor". "
George Coukos, who heads the Lausanne Branch of the Ludwig Institute for Cancer Research and led the study
Chemokines, the signaling proteins involved in the trafficking of various immune cells into the tumor microenvironment, help T cells to become lodged in tumors and can affect tumor immunity and therapeutic outcomes. But what chemokines are involved and how they interact with each other for this purpose is not well understood.
The study, published in the latest issue of the journal Cancer cell, identifies biomarkers that are very useful for cancer immunotherapy and could allow a more precise clinical clbadification of tumors. This could also inform the design of new types of cell-based immunotherapies and other immunotherapies for cancer. "These findings have helped to better understand how T-cell attack on tumors is orchestrated naturally in T-cell-inflamed tumors," said Denarda Dangaj, a postdoctoral researcher at Ludwig Lausanne, the author's first author. 39; section.
This recent study was motivated by the discovery in 2003 of the Coukos laboratory that patients with ovarian cancer whose tumors are infiltrated by killer T cells (or CD8 +) destroy infected cells. and cancerous and improve their survival. Other studies have shown similar correlations in most solid tumors.
In the present study, Coukos and his team identified two chemokines, CCL5 and CXCL9, consistently badociated with the infiltration of CD8 + T cells into solid tumors. They show that CCL5 is expressed by cancer cells, while CXCL9 is produced by other immune cells (called myeloid cells), called macrophages and dendritic cells, also present in the tumor. When cancer cells reduce their production of CCL5, the expression of CXCL9 also decreases. This results in a gradual decrease of CD8 + T cells in tumors.
They discovered that this loss of CCL5 expression in cancer cells is correlated with a chemical modification of DNA that suppresses the expression of targeted genes: a mechanism known as epigenetic silencing. The researchers suggest that the epigenetic silence of CCL5 is an adaptive mechanism by which tumors escape the immune attack.
Cancer cells have good reason to suppress CCL5: they attract CD8 + T cells. Researchers have shown that when T cells drawn by CCL5 reach the tumor and are activated by cancer antigens, they release a signaling protein called interferon gamma (IFNγ). They discovered that this causes the secretion of CXCL9 by macrophages and dendritic cells that have gathered at the tumor, which greatly accelerates the infiltration of the tumor by circulating T cells.
"CCL5 is the essential chemokine to determine if a tumor will be inflamed by T cells," said Coukos. "However, the expression of CCL5 alone is not sufficient and CXCL9 is a major enhancer of T cell recruitment."
These results suggest that CCL5 and CXCL9 may be useful biomarkers for immunotherapy. In particular, they could help identify patients whose tumors are infiltrated by activated T cells and are therefore more likely to be sensitive to immunotherapies such as anti-PD1 antibodies.
The newly discovered mechanism of immune evasion could also be exploited for therapeutic purposes. "Knowing that decitabine reduces the silence of CCL5 is a strong reason for badociating this epigenetic treatment with blocking PD1," says Coukos.
Source:
Ludwig Institute for Cancer Research
Journal reference:
Coukos, G. et al. (2019) The cooperation between constitutive and inducible chemokines allows T cell grafting and immune attack in solid tumors. Cancer cell. doi.org/10.1016/j.ccell.2019.05.004.
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