T cell help in the tumor microenvironment enhances rituximab-mediated NK cell ADCC

Rituximab (RTX) and other monoclonal antibodies (mAbs) that bind directly to malignant cells are of great clinical value but are not effective for all patients. A major mechanism of action of RTX is antibody dependent cellular cytotoxicity (ADCC) mediated by NK cells. Prior in vitro studies in our laboratory demonstrated that T cells contribute to maintaining the viability and cytotoxic potential of NK cells activated by anti-CD20-coated target B cells. Here, we conducted studies using a novel mouse model and clinical correlative analysis to assess whether T cell help contributes to RTX-mediated NK cell ADCC in the tumor microenvironment (TME) in vivo. A humanized mouse model was developed using Raji lymphoma cells and normal donor peripheral blood mononuclear cells that allows for control of T cell numbers in the lymphoma TME. In this model, NK cell viability, CD16 and CD25 expression dropped following RTX in the absence of T cells but increased in the presence of T cells. RTX therapy was more effective when T cells were present and was ineffective when NK cells were depleted. In indolent lymphoma patients, fine needle aspirates were obtained prior to and approximately one week after treatment with a RTX-containing regimen. There was a strong correlation between CD4+ T cells as well as total T cells in the pre-therapy TME, and an increase in NK cell CD16 and CD25 expression following RTX. We conclude that T cell help in the TME enhances RTX-mediated NK cell viability and ADCC.