title: Chimeric antigen receptor T cells targeting HERV-K inhibit breast cancer and its metastasis through downregulation of Ras.
abstract: We have previously reported that human endogenous retrovirus-K (HERV-K) envelope (env) protein is a tumor-associated antigen (TAA) for cancer vaccines, and that its antibodies (mAbs) possess antitumor activity against cancer. In this study, a chimeric antigen receptor (CAR) specific for HERV-K env protein (K-CAR) was generated using anti-HERV-K mAb. K-CAR T cells from peripheral blood mononuclear cells (PBMCs) of 9 breast cancer (BC) patients and 12 normal donors were able to inhibit growth of, and to exhibit significant cytotoxicity toward, BC cells but not MCF-10A normal breast cells. The antitumor effects in cancer cells were significantly reduced when control T cells were used, or the expression of HERV-K was knocked down by an shRNA. Secretion of multiple cytokines, including IFNγ, TNF-α, and IL-2, was significantly enhanced in culture media of BC cells treated with K-CARs. Significantly reduced tumor growth and tumor weight was observed in xenograft models bearing MDA-MB-231 or MDA-MB-435.eB1 BC cells. Importantly, the K-CAR prevented tumor metastasis to other organs. Furthermore, downregulation of HERV-K expression in tumors of mice treated with K-CAR correlated with upregulation of p53 and downregulation of MDM2 and p-ERK. Importantly, the expression of HERV-K env protein in metastatic tumor tissues treated with K-CAR T cells correlated with the expression of Ras. Our results indicate that HERV-K env protein is an oncoprotein and may play an important role in tumorigenesis related to p53 and Ras signaling pathways. Anti-HERV-K treatment, including K-CAR treatment, shows potential for immunotherapy of BC.
authors.affiliation: Department of Veterinary Sciences; University of Texas MD Anderson Cancer Center ; Houston, TX USA ; Viral Oncology Program; SRI International ; Menlo Park, CA USA ; Department of Clinical Hematology; Second Affiliated Hospital; School of Medicine; Xi'an Jiaotong University ; Xi'an, Shannxi, China.
authors.forename: Fuling
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Division of Pediatrics; University of Texas MD Anderson Cancer Center ; Houston, TX USA ; Graduate School of Biomedical Sciences ; Houston, TX USA.
authors.forename: Janani
authors.initials: J
authors.lastname: Krishnamurthy
authors.affiliation: Department of Veterinary Sciences; University of Texas MD Anderson Cancer Center ; Houston, TX USA ; Viral Oncology Program; SRI International ; Menlo Park, CA USA ; Department of Clinical Oncology, First Affiliated Hospital; School of Medicine; Xi'an Jiaotong University , Xi'an, Shannxi, China.
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Veterinary Sciences; University of Texas MD Anderson Cancer Center ; Houston, TX USA ; Viral Oncology Program; SRI International ; Menlo Park, CA USA ; Graduate School of Biomedical Sciences ; Houston, TX USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Surgical Oncology; University of Texas MD Anderson Cancer Center ; Houston, TX USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hunt
authors.affiliation: Department of Veterinary Sciences; University of Texas MD Anderson Cancer Center ; Houston, TX USA ; Viral Oncology Program; SRI International ; Menlo Park, CA USA ; Graduate School of Biomedical Sciences ; Houston, TX USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johanning
authors.affiliation: Division of Pediatrics; University of Texas MD Anderson Cancer Center ; Houston, TX USA ; Graduate School of Biomedical Sciences ; Houston, TX USA.
authors.forename: Laurence Jn
authors.initials: LJ
authors.lastname: Cooper
authors.affiliation: Department of Veterinary Sciences; University of Texas MD Anderson Cancer Center ; Houston, TX USA ; Viral Oncology Program; SRI International ; Menlo Park, CA USA ; Graduate School of Biomedical Sciences ; Houston, TX USA ; Department of Immunology; University of Texas MD Anderson Cancer Center ; Houston, TX USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang-Johanning
keywords: HERV-K; and Ras; breast cancer; chimeric antigen receptor; metastasis