Cancer Immunotherapy Therapeutic Manipulation of the CD8-HLA Class I Interaction: Potential and Challenges

The interaction between CD8 and HLA class I is largely monomorphic and of low affinity. Previous studies have indicated that changing the affinity of this interaction can have dramatic biological effects. Reductions in CD8-HLA class I binding affinity can lead to inhibition of T cell mediated target cell killing, whilst modest affinity increases lead to enhanced target cell killing with retained antigenic specificity. Here it is shown that target cells bearing a high affinity chimeric MHC molecule termed a ‘Supertarget’ comprising the HLA-A2 molecule incorporating the murine MHC Kb alpha 3 domain can be killed by T cells irrespective of their native HLA or peptide specificity. We will review the immunotherapy potential of this Supertarget protein and also how novel drugs acting as agonists or antagonists at the CD8-HLA class I interface could have clinical potential.