MSGID: 1:317/3 6279ea7c   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    T cell behavior determines which tumors respond to treatment    
      
     Date:   
         May 9, 2022   
     Source:   
         Weill Cornell Medicine   
     Summary:   
         Immunotherapy unleashes the power of the immune system to fight   
         cancer.   
      
         However, for some patients, immunotherapy doesn't work, and   
         new research may help explain why. When immune cells called T   
         lymphocytes infiltrate malignant tumors, the genetic program   
         of those T cells and the developmental path they then follow,   
         may affect their response to immunotherapy and predict overall   
         patient survival, according to a new study. The results overturn   
         the prevailing model of immune responses in melanoma and present   
         different therapeutic approaches.   
      
      
      
   FULL STORY   
   ==========================================================================   
   Immunotherapy unleashes the power of the immune system to fight cancer.   
      
   However, for some patients, immunotherapy doesn't work, and new   
   research may help explain why. When immune cells called T lymphocytes   
   infiltrate malignant tumors, the genetic program of those T cells and   
   the developmental path they then follow, may affect their response to   
   immunotherapy and predict overall patient survival, according to a new   
   study by Weill Cornell Medicine investigators. The results overturn the   
   prevailing model of immune responses in melanoma and present different   
   therapeutic approaches.   
      
      
   ==========================================================================   
   In the study, published May 9 in Cancer Cell, the investigators analyzed   
   thousands of human tumor samples, plus individual human T cells across   
   many data sets and tumor types, and compared these to many models of T   
   cell behavior in response to infections, cancer and vaccines, including   
   human vaccines. They found that T cells either become stuck in an early   
   activation state or develop into memory cells that are expanded by   
   current immunotherapy approaches.   
      
   "The T cells don't behave in a singular manner, but we can understand   
   their behavior and model it in a way that can predict patient outcomes   
   and overall survival," said senior author Dr. Niroshana Anandasabapathy,   
   associate professor of dermatology and of dermatology in microbiology and   
   immunology at Weill Cornell Medicine, and a practicing dermatologist for   
   melanoma patients at NewYork-Presbyterian/Weill Cornell Medical Center.   
      
   Scientists have long known that the immune system can detect and eliminate   
   tumor cells on its own, but this process sometimes breaks down, leading   
   to the development of cancer. Previous data seemed to support a theory in   
   which, once a tumor is established, T lymphocytes entering the tumor keep   
   seeing and responding to tumor proteins until they become exhausted and   
   unable to attack the cancerous cells. That theory was used to explain   
   the success of a type of therapy called immune checkpoint blockade,   
   which uses cellular signals to improve T cell responses, reawakening   
   the T cells' ability to attack and eliminate the tumor.   
      
   Some patients' tumors don't respond to immune checkpoint blockade,   
   though. To figure out why, the team began looking at larger data sets   
   and analyzing them more broadly than previous studies.   
      
   "We wanted to take an entirely agnostic approach to trying to understand   
   what happens to a T cell when it enters the tumor microenvironment -- a   
   really naive, unbiased approach," said Dr. Anandasabapathy, who is also   
   a member of the Sandra and Edward Meyer Cancer Center and the Englander   
   Institute for Precision Medicine.   
      
   By using large programs of many genetic markers and multiple, simultaneous   
   genomic strategies to categorize cell fates, Dr. Anandasabapathy and   
   her collaborators were able to re-classify T cells in tumors, and better   
   model how they develop. The results show that infiltrating T cells don't   
   all meet the same fate in every tumor. In contrast to the standard view,   
   a "failure to launch" beyond early activation and convert to memory, and   
   not exhaustion appeared to be the problem. The enrichment of long-lived   
   memory programs correlates strongly with overall survival and a successful   
   response to immune checkpoint blockade therapy in melanoma.   
      
   In addition to predicting outcomes, the investigators hope to find ways   
   to change them. Getting T cells past their failure to launch and inducing   
   the formation of tumor-infiltrating memory T cells in patients who lack   
   them, for example, could make non-responsive tumors sensitive to immune   
   checkpoint blockade.   
      
   While the current work focused on malignant melanoma, the scientists   
   also identified that similar phenomena likely underlie differences in   
   patient T cell responses to other types of cancer, including kidney,   
   bladder, prostate and liver cancer.   
      
   "The power of the study is really in opening new avenues of discovery   
   and suggesting more rational therapeutics," said first author Abhinav   
   Jaiswal, a doctoral candidate at Weill Cornell Graduate School of Medical   
   Sciences in Dr.   
      
   Anandasabapathy's laboratory.   
      
      
   ==========================================================================   
   Story Source: Materials provided by Weill_Cornell_Medicine. Note:   
   Content may be edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Abhinav Jaiswal, Akanksha Verma, Ruth Dannenfelser, Marit Melssen,   
      Itay   
         Tirosh, Benjamin Izar, Tae-Gyun Kim, Christopher J. Nirschl,   
         K. Sanjana P. Devi, Walter C. Olson, Craig L. Slingluff,   
         Victor H. Engelhard, Levi Garraway, Aviv Regev, Kira Minkis,   
         Charles H. Yoon, Olga Troyanskaya, Olivier Elemento, Mayte   
         Sua'rez-Farin~as, Niroshana Anandasabapathy. An activation to   
         memory differentiation trajectory of tumor-infiltrating lymphocytes   
         informs metastatic melanoma outcomes. Cancer Cell, 2022; 40 (5):   
         524 DOI: 10.1016/j.ccell.2022.04.005   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2022/05/220509132630.htm   
      
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