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    Surprise finding shows that neutrophils can be key antitumor weapons   
      
      
     Date:   
         March 30, 2023   
     Source:   
         Weill Cornell Medicine   
     Summary:   
         White blood cells called neutrophils have an unappreciated role   
         in eradicating solid tumors, according to a surprise discovery.   
      
      
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   FULL STORY   
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   White blood cells called neutrophils have an unappreciated role in   
   eradicating solid tumors, according to a surprise discovery from a team   
   led by Weill Cornell Medicine scientists.   
      
      
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   In the study, published March 30 in Cell, the researchers investigated   
   how a T cell-based immunotherapy was able to destroy melanoma tumors   
   even though many of the tumor cells lacked the markers or "antigens"   
   targeted by the T cells.   
      
   They found that the T cells, in attacking the tumors, activated a swarm   
   of neutrophils -- which in turn killed the tumor cells that the T cells   
   couldn't eliminate. The findings could lead to new immunotherapies that   
   harness this unexpected but potent antitumor immune response.   
      
   "We have tended to think of innate cells as immune cells that, at best,   
   can help stimulate an initial T cell response to a tumor. In addition,   
   many studies have shown that neutrophils support tumor progression, but   
   here we reveal that they can have a critical role in eliminating and   
   finishing off a tumor that would otherwise escape a T cell therapy,"   
   said study co-senior author Dr. Taha Merghoub, deputy director of the   
   Sandra and Edward Meyer Cancer Center, the Margaret and Herman Sokol   
   Professor of Oncology Research and a professor of pharmacology at Weill   
   Cornell Medicine, and co-director of the Ludwig Collaborative Laboratory.   
      
   "This work clearly shows us that the monolithic term 'neutrophil'   
   needs to be more specific, based on the use of single-cell technology,"   
   said co-senior author Dr. Jedd Wolchok, the Meyer Director of the Meyer   
   Cancer Center and a professor of medicine at Weill Cornell Medicine,   
   co-director of the Ludwig Collaborative Laboratory and an oncologist at   
   NewYork-Presbyterian/Weill Cornell Medical Center. "In the past, this   
   general term referred to a population of cells that were not thought to   
   be helpful in controlling tumors.   
      
   We now know that a subset of these cells is critical in optimizing   
   engineered T cell therapies to overcome heterogeneity."  Cancer   
   immunotherapies, which harness or boost immune cells' ability to   
   attack malignant cells, have begun to revolutionize cancer treatment   
   over the past decade. In some cases, these therapies have essentially   
   cured advanced cancer patients who would have had no hope of survival   
   otherwise. Yet for most cancers, immunotherapies are effective in only a   
   minority of patients. In general, researchers still have much to learn   
   about how anticancer immunotherapies work and how their effectiveness   
   can be improved.   
      
   In the study, the researchers investigated an experimental immunotherapy   
   that includes a drug to boost T cell activity and proliferation, plus   
   T cells that have been engineered to recognize a melanoma-associated   
   antigen. Tumors sometimes can evade an immunotherapy targeting a specific   
   tumor antigen simply by ceasing to express that antigen -- the tumor cells   
   that don't express the antigen are called "escape variants." However,   
   the researchers found that their boosted T cell therapy could eliminate   
   melanomas, in standard mouse models, even when a large portion of the   
   melanoma cells lacked the targeted antigen, Trp1.   
      
   Ultimately, they determined that the initial anti-tumor activity   
   of the T cells against Trp1-expressing melanoma cells triggered a   
   secondary tumor-killing response -- from neutrophils. These white   
   blood cells are best known as first- responders to infections and   
   wounds. As members of the evolutionary older "innate" immune system,   
   they do not target specific antigens in the way that T cells do. Yet   
   the researchers concluded that the neutrophils summoned by their T-cell   
   immunotherapy were indeed responsible for killing off the remaining,   
   non-Trp1-expressing melanoma cells -- at least in part by secreting the   
   highly reactive molecule nitric oxide.   
      
   As part of the study, the researchers identified a characteristic gene   
   expression pattern in the antitumor neutrophils, and found that in a   
   widely used database on melanoma patients, the greater presence of this   
   gene- expression "signature" in biopsied tumor samples was associated   
   with better outcomes for patients.   
      
   The results were especially surprising because prior studies have shown   
   that neutrophils around a tumor often act as allies of the tumor --   
   the tumor co- opts them to help it survive and spread, which they do in   
   part by suppressing other elements of antitumor immunity.   
      
   In any case, the new findings suggest that in the context of a strong   
   immunotherapy that includes engineered T-cells targeting tumor antigens,   
   and a general boosting of T-cell functions, neutrophils can play a   
   significant antitumor role -- in fact, an essential role in mopping up   
   escape variant tumor cells that would otherwise keep the tumor alive.   
      
   "Conventional T cell-based therapies have been successful in treating   
   cancers, but they are not as effective against heterogenous tumors,   
   which have antigen escape variants that can be invisible to the   
   immune system," said Dr. Daniel Hirschhorn, an assistant professor of   
   research in pharmacology at Weill Cornell Medicine. "It was incredibly   
   surprising to discover that T cell-educated neutrophils can eliminate   
   these 'invisible' tumor cells. This discovery highlights the importance   
   of mobilizing multiple arms of the immune system in the fight against   
   cancer."  The researchers now are continuing to study these anti-tumor   
   neutrophils, to determine how they can best be induced and directed --   
   as cancer-fighters on their own, or as enhancers of other immunotherapies.   
      
   "I also hope that we can find a way to use measures of these antitumor   
   neutrophils in tumor biopsies as biomarkers that help us choose the best   
   therapies for patients," Dr. Merghoub said.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Brain_Tumor # Cancer # Skin_Cancer # Lung_Cancer #   
                   Immune_System # Lymphoma # Stem_Cells # Colon_Cancer   
       * RELATED_TERMS   
             o White_blood_cell o Blood o Leukemia o Histamine o Brain_tumor   
             o Bone_marrow o Natural_killer_cell o Glycogen   
      
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   Story Source: Materials provided by Weill_Cornell_Medicine. Note:   
   Content may be edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Daniel Hirschhorn et al. T cell immunotherapies engage neutrophils   
      to   
         eliminate tumor antigen escape variants. Cell, 2023 DOI: 10.1016/   
         j.cell.2023.03.007   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/03/230330122805.htm   
      
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