Depletion of B220+NK1.1+ cells enhances the rejection of established melanoma by tumor-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+ cells enhances the rejection of established melanoma tumors by adoptively transferred TRP-1 CD4+ T cells. NK1.1+ cell depletion increases the number of CD4+ T cells, the serum concentration of pro-inflammatory cytokines, autoimmune vitiligo, host survival and prevented recurrence after ACT. Because multiple cells express NK1.1, we targeted different NK1.1+ cell populations using antibodies specific for NK cells, pre-mNK cells, and innate lymphoid cells (ILCs). Our data suggests that NK1.1+B220+ pre-mNK cells (also known as interferon-producing killer dendritic cells; IKDCs) are an important inhibitor of the CD4+ T cell response to melanoma. Understanding this mechanism may help design new immunotherapies to modulate the activity of pre-mNKs in the face of an antitumor immune response and inhibit their suppression of adoptively transferred T cells.