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T cell receptor affinity and avidity defines antitumor response and autoimmunity in T cell immunotherapy
  1. Michelle Krogsgaard1,3,7,
  2. Shi Zhong1,
  3. Karolina Malecek1,6,
  4. Laura A Johnson5,
  5. Zhiya Yu2,
  6. Eleazar Vega-Saenz de Miera7,3,
  7. Farbod Darvishian3,
  8. Katelyn McGary-Shipper1,6,
  9. Kevin Huang1,
  10. Joshua Boyer1,
  11. Emily Corse4,
  12. Yongzhao Shao8,7,
  13. Steven A Rosenberg2,
  14. Nicholas P Restifo2 and
  15. Iman Osman1,9,7
  1. Aff1 grid.137628.90000000121698901NYU Cancer InstituteNew York University School of Medicine New York NY USA
  2. Aff2 grid.48336.3a0000000419368075Center for Cancer Research, National Cancer InstituteNational Cancer Institute, NIH Bethesda MD USA
  3. Aff3 grid.137628.90000000121698901Department of PathologyNew York University School of Medicine New York NY USA
  4. Aff4 grid.240145.60000000122914776Department of ImmunologyThe University of Texas MD Anderson Cancer Center Houston TX USA
  5. Aff5 grid.25879.310000000419368972Abramson Family Cancer Research Institute, Perelman School of MedicineUniversity of Pennsylvania Philadelphia PA USA
  6. Aff6 grid.137628.90000000121698901Program in Structural BiologyNew York University School of Medicine New York NY USA
  7. Aff7 grid.137628.90000000121698901Interdisciplinary Melanoma Cooperative GroupNew York University School of Medicine New York NY USA
  8. Aff8 grid.137628.90000000121698901Division of BiostatisticsNew York University School of Medicine New York NY USA
  9. Aff9 grid.137628.90000000121698901Ronald O. Perelman Department of DermatologyNew York University School of Medicine New York NY USA

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Meeting abstracts

T-cells have evolved the unique ability to discriminate "self" from "non-self" with high sensitivity and selectivity. However, tissue-specific autoimmunity, tolerance or eradication of cancer does not fit into the self/non-self paradigm because the T-cell responses in these situations are most often directed to non-mutated self-proteins. To determine the TCR affinity threshold defining the optimal balance between effective antitumor activity and autoimmunity in vivo, we used a novel self-antigen system comprised of seven human melanoma gp100209-217-specific TCRs spanning physiological affinities (1 to 100 μM). We found that in vitro and in vivo T cell responses are determined by TCR affinity. Strikingly, we found that T cell antitumor activity and autoimmunity are closely coupled but plateau at a defined TCR affinity of 10 µM, likely due to diminished contribution of TCR affinity to avidity above the threshold. Our results suggest a relatively low affinity threshold is necessary for the immune system to avoid self-damage given the close relationship between antitumor activity and autoimmunity. This, in turn, indicates that treatment strategies focusing on TCRs in the intermediate affinity range (KD ~10 μM) or targeting or targeting shared tumor antigens would dampen the potential for autoimmunity during adoptive T cell therapy for the treatment of cancer.