title: CD4+ T cell-mediated cytotoxicity eliminates primary tumor cells in metastatic melanoma through high MHC class II expression and can be enhanced by inhibitory receptor blockade.
abstract: Metastatic melanoma is a rapidly progressing disease with high mortality rate and limited treatment options. Immunotherapy based on tumor-targeting cytotoxic T cell responses represents a promising strategy. To assist in its development, we examined the possibility and efficacy of using CD4+cytotoxic T cells. The regulatory mechanisms controlling CD4+T cell-mediated cytotoxicity were also investigated. We found that naturally occurring granzyme B and perforin-expressing CD4+cytotoxic T cells can be recovered from metastatic melanoma patients at significantly elevated frequencies compared to those from healthy controls. These CD4+cytotoxic T cells were also capable of killing autologous tumor cells harvested from metastatic melanoma, independent of CD8+T cells or any other cell types. However, several restricting factors were observed. First, the cytolytic activity by CD4+T cells required high MHC class II expression on melanoma cells, which was not satisfied in a subset of melanomas. Second, the granzyme B and perforin release by activated CD4+cytotoxic T cells was reduced after coculturing with autologous melanoma cells, characterized by low LAMP-1 expression and low granzyme B and perforin secretion in the supernatant. This suggested that inhibitory mechanisms were present to suppress CD4+cytotoxic T cells. Indeed, blockade of PD-1 and CTLA-4 had increased the cytolytic activity of CD4+T cells but was only effective in MHC class II high but not MHC class II low melanomas. Together, our study showed that CD4+T cell-mediated cytotoxicity could eliminate primary melanoma cells but the efficacy depended on MHC class II expression.
authors.affiliation: Department of Dermatology, The First People's Hospital of Jining City, 6 Jiankang Road, Jining, Shangdong, 272011, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Supply and Services, Jiaxiang County People's Hospital, Jiaxiang County, Jining, Shangdong, 272400, China.
authors.forename: Xianglian
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Dermatology, The First People's Hospital of Jining City, 6 Jiankang Road, Jining, Shangdong, 272011, China. tianhangli_jn@sina.com.
authors.forename: Tianhang
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Dermatology, The First People's Hospital of Jining City, 6 Jiankang Road, Jining, Shangdong, 272011, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: DICAT Biomedical Computation Centre, Vancouver, BC, Canada.
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Dermatology, The First People's Hospital of Jining City, 6 Jiankang Road, Jining, Shangdong, 272011, China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Dermatology, The First People's Hospital of Jining City, 6 Jiankang Road, Jining, Shangdong, 272011, China.
authors.forename: Ruijie
authors.initials: R
authors.lastname: Zhu
keywords: CD4+ T cell; MHC class II; Melanoma