Tumor Biology

, Volume 37, Issue 12, pp 15949–15958 | Cite as

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

  • Hongxia Yan
  • Xianglian Hou
  • Tianhang Li
  • Li Zhao
  • Xiaozhou Yuan
  • Hongjun Fu
  • Ruijie Zhu
Original Article


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.


Melanoma CD4+ T cell MHC class II 


Compliance with ethical standards

Ethics statement

The ethics review board of Jining The First People’s Hospital approved the use of human samples and procedures. Written informed consent was obtained from all subjects.

Conflict of interest



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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Hongxia Yan
    • 1
  • Xianglian Hou
    • 2
  • Tianhang Li
    • 1
  • Li Zhao
    • 1
  • Xiaozhou Yuan
    • 3
  • Hongjun Fu
    • 1
  • Ruijie Zhu
    • 1
  1. 1.Department of DermatologyThe First People’s Hospital of Jining CityJiningChina
  2. 2.Department of Supply and ServicesJiaxiang County People’s HospitalJiningChina
  3. 3.DICAT Biomedical Computation CentreVancouverCanada

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