Investigating the effect of anti-CTLA-4 on tumor-infiltrating effector T cells

Despite the relative success of checkpoint inhibitors, a majority of patients fail to respond to these therapies. Thus it is necessary to understand mechanisms of resistance in order to extend the benefits of immunotherapy to more patients. Checkpoint inhibitors are designed to prevent the interaction of immune checkpoints with their ligands, thereby allowing the body’s anti-tumor immune response to be reactivated. Recently, it has been appreciated that anti-CTLA4 therapies, including Ipilimumab, have a second mode of action. They can mediate antibody-dependent cell-mediated cytotoxicity (ADCC). This leads to death of cells bound by anti-CTLA4. While CTLA4 is largely intracellular, it is expressed on the surface of tumor-infiltrating T regulatory cells (Tregs). Thus anti-CTLA4-mediated ADCC can deplete tumor-infiltrating Tregs. In mice, ADCC of tumor-infiltrating Tregs is required for anti-CTLA4 efficacy. Likewise, Ipilimumab can mediate Fc-receptor dependent depletion of human Tregs. We have found that a portion of effector T cells infiltrating mouse and human tumors express surface CTLA-4 at levels similar to tumor-infiltrating Tregs. We further find that this portion of tumor-infiltrating effector T cells is likely to include tumor-reactive T cells. We will discuss the possibility that anti-CTLA4 can lead to Fc-receptor-dependent depletion of effector T cells and the implications for therapy resistance.