Chimeric NKG2D receptor expressing T cells require host immune cells for anti‐tumor efficacy

Abstract

We have developed a chimeric NKG2D receptor (chNKG2D) consisting of NKG2D fused to the CD3ζ chain of the T cell receptor and have shown that chNKG2D therapy can be an effective treatment in murine models of lymphoma and ovarian carcinoma. In this study, we demonstrate the key mechanisms that chNKG2D T cells require and a role for the host immune system in tumor elimination. Treatment of B6 mice with chNKG2D T cells led to long‐term, tumor‐free survival in a murine ovarian cancer model. ChNKG2D T cells were required to produce perforin, IFNγ, and GM‐CSF for complete efficacy in vivo. Additionally, chNKG2D T cell treatment led to an increased number and activation of host NK cells at the tumor site. Inhibition of tumor growth was limited in host mice that lacked perforin or T and B cells (Rag1‐/‐), indicating that host immune mechanisms were involved. There was no role for CD1‐dependent NKT cells or GM‐CSF, as mice deficient in these were able to clear tumors as well as wildtype B6 mice. In summary, treatment with chNKG2D T cells led to long‐term survival of mice with established ovarian cancer, and chNKG2D T cells required cytotoxicity, cytokine secretion, and the participation of host immune cells for complete anti‐tumor efficacy. This work was supported in part by grants from the Norris Cotton Cancer Center and National Institutes of Health (AI 07363).