Cancer cell: research reveals the cytokines that determine T cell colonization and attack tumors!

June 13, 2019 / BIOON / - a study by Ludwig cancer research has cracked the complex molecular dialogue between cancer and immune cells, which is the key for T cells to successfully invade and kill cancer cells "We demonstrated that two key chemokines, CCL5 and CXCL9, are prevalent in T cell infiltration in all solid tumors," said George coukos, director of the Lausanne branch of the Ludwig Cancer Institute and head of the study "Their simultaneous presence in tumors is a key condition for T cell transplantation and the formation of T cell inflammatory tumors (also known as' hot tumors') "Image source: cancer cell chemokine is a signaling protein that mediates the entry of various immune cells into the tumor microenvironment, helps T cells locate in the tumor, and can affect tumor immunity and treatment results However, which chemokines are involved and how they interact to achieve this goal have not been well understood The study, published in the latest issue of cancer cell, identifies biomarkers that are closely related to cancer immunotherapy and may lead to more accurate clinical classification of tumors It can also provide reference for the design of new cell therapy and other cancer immunotherapy "These findings enhance our understanding of how T cells in inflammatory T-cell tumors coordinate their attack on tumors," said denarda dangaj, lead author of the paper and a postdoctoral researcher at the University of Ludwig Lausanne This latest study was driven by the findings of coukos laboratory in 2003, which showed that the survival rate of ovarian cancer patients with tumor infiltrated by killer cells (or CD8 + T cells) increased, while killer cells (or CD8 + T cells) can destroy infected cells and cancer cells Other studies have found similar correlations in most solid tumors In the current study, coukos and his team found two chemokines, CCL5 and CXCL9, which are consistent with CD8 + T cell infiltration in solid tumors They show that CCL5 is expressed by cancer cells, while CXCL9 is produced by other (so-called myeloid) immune cells (macrophages and dendritic cells), which are also present in tumors CXCL9 expression also decreased when cancer cells reduced CCL5 production This leads to the gradual depletion of CD8 + T cells in tumors They found that the loss of CCL5 expression in cancer cells is linked to chemical modifications of DNA that inhibit the expression of targeted genes - a mechanism known as epigenetic silencing The researchers believe that the epigenetic silencing of CCL5 is an adaptive mechanism for tumor to evade immune attack Cancer cells have good reason to inhibit CCL5: it attracts CD8 + T cells Researchers have shown that when T cells reach tumors through CCL5 and are activated by cancer antigens, they release their own signaling protein, interferon gamma (IFN γ) They found that this led to the secretion of CXCL9 by macrophages and dendritic cells that gathered on the tumor, which significantly promoted tumor infiltration through circulating T cells "CCL5 is a key chemokine that determines whether a tumor will be infected by T cells," coukos said "However, expression of CCL5 alone is not enough, CXCL9 is the main amplifier for T cell recruitment "These findings suggest that CCL5 and CXCL9 may be useful biomarkers for immunotherapy Most notably, they can help identify patients with tumor activated T cell infiltration and are therefore more susceptible to immunotherapies such as anti-pd1 antibodies The newly discovered immune escape mechanism may also be used for treatment "We know that the silencing of CCL5 can be reversed by the drug dessicabine, which provides a strong theoretical basis for the combination of epigenetic therapy and PD1 blockade," coukos said "Reference: denarda dangaj et al, cooperation between constructive and induced chemicals enables T cell engraftment and immune attack in solid tumors, cancer cell (2019) Doi: 10.1016/j.ccell.2019.05.004