title: Collaboration of chimeric antigen receptor (CAR)-expressing T cells and host T cells for optimal elimination of established ovarian tumors.
abstract: Conditioning strategies that deplete host lymphocytes have been shown to enhance clinical responses to some adoptive T-cell therapies. However, host T cells are capable of eliminating tumor cells upon the relief of immunosuppression, indicating that lymphodepletion prior to T-cell transfer may reduce optimal tumor protection elicited by cell treatments that are capable of shaping host immunity. In this study, we show that adoptively transferred T cells bearing a chimeric antigen receptor (CAR) harness endogenous T cells for optimal tumor elimination and the development of a tumor-specific memory T cell response. Mice bearing ID8 ovarian cancer cells were treated with T cells transduced with a NKG2D-based CAR. CAR-expressing T cells increased the number of host CD4+and CD8+T cells at the tumor site in a CXCR3-dependent manner and increased the number of antigen-specific host CD4+T cells in the tumor and draining lymph nodes. In addition, the administration of CAR-expressing T cells increased antigen presentation to CD4+T cells, and this increase was dependent on interferon γ and granulocyte-macrophage colony-stimulating factor produced by the former. Host CD4+T cells were sufficient for optimal tumor protection mediated by NKG2D CAR-expressing T cells, but they were not necessary if CD4+T cells were adoptively co-transferred. However, host CD4+T cells were essential for the development of an antigen-specific memory T-cell response to tumor cells. Moreover, optimal tumor elimination as orchestrated by NKG2D CAR-expressing T cells was dependent on host CD8+T cells. These results demonstrate that adoptively transferred T cells recruit and activate endogenous T-cell immunity to enhance the elimination of tumor cells and the development of tumor-specific memory responses.
authors.affiliation: Department of Microbiology & Immunology; The Geisel School of Medicine at Dartmouth; Lebanon, NH USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Spear
authors.forename: Amorette
authors.initials: A
authors.lastname: Barber
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sentman
keywords: CD4+ T cells; CD8+ T cells; ID8; NKG2D; adoptive T cell therapy; chNKG2D; immunotherapy; ovarian cancer; tumor immunology