MSGID: 1:317/3 64a6437e   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Immune and tumor cell 'tug-of-war' controls anti-cancer activity    
      
     Date:   
         July 5, 2023   
     Source:   
         St. Jude Children's Research Hospital   
     Summary:   
         Scientists have found that altering amounts of the nutrient   
         glutamine in the tumor microenvironment could enhance or impair   
         the immune system's anti-cancer response.   
      
      
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   Scientists at St. Jude Children's Research Hospital found immune and   
   tumor cells compete over glutamine, a major nutrient in their local   
   environment, with significant implications for anti-cancer activity. If   
   cancer cells monopolize glutamine, they can prevent immune cells from   
   destroying cancer. The findings show that supplying glutamine directly to   
   tumors helps initiate the immune system's cancer-killing activity. The   
   researchers also identified a molecular pathway that could serve as a   
   potential drug target to achieve the same effect.   
      
   The findings were published today in Nature.   
      
   "It's a nutrient tug-of-war between tumor cells and immune cells,"   
   said corresponding author Hongbo Chi, Ph.D., St. Jude Department of   
   Immunology. "If tumor cells use all the available glutamine, then a   
   specialized immune cell type known as the dendritic cell is starved of   
   glutamine, leading to impaired anti-tumor immune function. But if we can   
   supplement enough glutamine to the tumor microenvironment, that will   
   inhibit tumor growth because dendritic cells will use it and activate   
   the adaptive immune response." Dendritic cells turn on cancer-killing   
   immune cells called T cells.   
      
   The group showed that resupplying glutamine in the tumor microenvironment   
   severely reduced tumor growth because dendritic cells were then better   
   able to activate anti-cancer T cells. The tumor microenvironment   
   is composed of chemicals and cells around cancer cells. Infamously,   
   cancer cells secrete many signals to turn the immune response "off" in   
   this area, especially the T cells that threaten their destruction. The   
   St. Jude team is the first to identify a nutrient as a major signal   
   between cancer cells and dendritic cells in this local environment.   
      
   Improving anti-cancer therapies "We are very excited to establish the link   
   between glutamine, therapeutic effect and dendritic cells," said first   
   author Chuansheng Guo, Ph.D., St. Jude Department of Immunology. "It's   
   critical for the efficacy of immune checkpoint blockade and adoptive   
   cell transfer therapy."  Immune checkpoint blockade therapy inhibits the   
   "off" signals cancer cells send to immune cells that suppress the immune   
   response in the tumor microenvironment. These therapies have been highly   
   effective, but only in a small number of patients. The researchers found   
   that supplying glutamine in combination with checkpoint therapy enhanced   
   anti-cancer activity in mice.   
      
   "This paper provides a proof of concept that nutrients could act   
   synergistically with checkpoint inhibitors for tumor treatment as a new   
   strategy for combination therapy," Chi said.   
      
   The mechanism of helping or hindering cancer-killing While much cancer   
   research has focused on T cells because of their direct cancer-killing   
   activity, this study is one of the first to examine how the tumor   
   microenvironment affects the dendritic cells, which activate T cells. The   
   researchers found that without glutamine, dendritic cells failed to   
   activate the T cells that directly kill cancer cells.   
      
   "Even though T cells are the cornerstone for anti-cancer immunity,   
   they cannot do the job by themselves," Chi explained. "We can think   
   of dendritic cells as the driver and the T cell as the car. If you   
   do not have a driver, the car will not move. Moreover, nutrients like   
   glutamine serve as the license for the driver."  Similarly, when the   
   researchers removed the proteins that respond to or take up glutamine   
   in dendritic cells, the immune cells failed to activate cancer- killing   
   cells. These proteins, called FLCN and SLC38A2, are important in sensing   
   and acquiring nutrients but have not previously been connected to immune   
   cells' reactions to tumors. They may serve as potent drug targets to   
   improve cancer therapy.   
      
   "We're extremely excited about these findings," Chi said. "In addition   
   to enhancing the therapeutic intervention, we have provided a conceptual   
   advance by showing how nutrients mediate cell-cell communication, an   
   understudied concept in the field of immunometabolism."  The study's   
   other authors are Zhiyuan You, Hao Shi, Gustavo Palacios, Cliff Guy,   
   Sujing Yuan, Nicole Chapman, Seon Ah Lim, Xiang Sun, Jordy Saravia,   
   Sherri Rankin, Yogesh Dhungana, of St. Jude, and Yu Sun and Xingrong Du,   
   formerly of St. Jude.   
      
   The study was supported by grants from the National Institutes of Health   
   (AI105887, AI131703, AI140761, AI150241, AI150514 and CA253188) and ALSAC,   
   the fundraising and awareness organization of St. Jude.   
      
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   Journal Reference:   
      1. Guo, C., You, Z., Shi, H. et al. SLC38A2 and glutamine signalling in   
         cDC1s dictate anti-tumour immunity. Nature, 2023 DOI:   
         10.1038/s41586-023- 06299-8   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230705143007.htm   
      
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