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
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 + cytoto...
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Published in | Tumor biology Vol. 37; no. 12; pp. 15949 - 15958 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Dordrecht
Springer Netherlands
01.12.2016
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1010-4283 1423-0380 |
DOI: | 10.1007/s13277-016-5456-5 |