NK1.1+B220+ Cell Depletion Enhances the Rejection of Established Melanoma by TAA-Specific CD4+ T Cells

Abstract

Five-year survival rates for patients diagnosed with metastatic melanoma are less than 5%. Adoptive cell transfer (ACT) has achieved an objective response of 50% by Response Evaluation Criteria in Solid Tumors (RECIST) in this patient population. For ACT to be maximally effective, the host must first be lymphodepleted. It is hypothesized that lymphodepletion may remove regulatory elements and cytokine sinks, or increase the activation and availability of antigen presenting cells (APCs). We use an in vivo model to study the ACT of tumor-associated antigen (TAA)-specific CD4+ T cells (TRP-1 cells). We have discovered that depletion of NK1.1+ and B220+ cells enhances the rejection of established melanoma tumors by adoptively transferred TRP-1 cells. Our data suggest that the most likely cell population responsible for suppressing the activity of adoptively transferred TRP-1 cells is premature natural killer (pre-mNK) cells. NK1.1+ cell depletion increases the number of TRP-1 cells, the serum concentration of pro-inflammatory cytokines, and host survival after ACT. Our data suggest that NK1.1+ cells use an NKG2D- and programmed death-ligand 1 (PD-L1)- dependent mechanism to suppress the activity of adoptively transferred TRP-1 cells. We believe that future ACT therapy designs should include a regimen to encourage an anti-tumor rather than pro-tumor immune response from NK1.1+B220+ cells.