Abstract
The inhibitory immune checkpoint PD-L1/PD1 promotes the alternative splicing of the FKBP5 gene, resulting in increased expression of its variant 4 in the peripheral blood mononuclear cells of melanoma patients. The variant 4 transcript is translated into the truncated FKBP51s protein. Given the importance of co-inhibitory signalling in tumour immune escape, here we tested the potential for using FKBP51s expression to predict immunotherapy outcomes. To do this, we immunophenotyped PBMCs from 118 melanoma patients and 77 age- and sex-matched healthy controls. Blood samples were collected before patients underwent ipilimumab treatment. In 64 of the 118 patients, FKBP51s expression was also assessed in regulatory T cells (Tregs). We found that each PBMC subset analysed contained an FKBP51spos fraction, and that this fraction was greater in the melanoma patients than healthy controls. In CD4 T lymphocytes, the FKBP51sneg fraction was significantly impaired. Tregs count was increased in melanoma patients, which is in line with previous studies. Also, by analyses of FKBP51s in Tregs, we identified a subgroup of ipilimumab nonresponder patients (p=0.002). In conclusion, FKBP51s-based immunophenotyping of melanoma patients revealed several profiles related to a negative immune regulatory control and identified an unknown Treg subset. These findings are likely to be useful in the selection of the patients that are candidate for immunotherapy.
Highlights
FK506 binding protein 51 (FKBP51) (FKBP5 Official Symbol) is a large molecular weight component of the family of FK506 binding proteins (FKBP)
The enhanced tumorigenic potential of melanoma cells is accompanied by increased levels of FKBP51 and Transforming growth factor-β (TGF-β) We have previously shown that SAN melanoma cells injected into the tail vein of immunosuppressed mouse produced significant liver and lung colonization within 4 weeks, and such invasive potential was strictly dependent on the expression of FKBP51 [4]
FKBP51 silencing produced a reduction of TGF-β and TGF-β receptor type III (TβRIII) gene expression in A375 cell line (Figure 1A), which is in accordance with the upregulation of these genes by FKBP51 [4]
Summary
FKBP51 (FKBP5 Official Symbol) is a large molecular weight component of the family of FK506 binding proteins (FKBP). Research studies from our laboratory highlighted functions for FKBP51 in the control of apoptosis and melanoma progression. FKBP51 expression correlated with the invasiveness and aggressiveness of melanoma. Since a role for TGF-β in the enhanced tumorigenic potential of melanoma cells is widely described, we hypothesized a cooperative effect between FKBP51 and TGF-β in melanoma progression. FK506 binding protein 51 (FKBP51) [1] is an immunophilin physiologically expressed in lymphocytes and several other tissues [2]. FKBP51 structure includes C-terminal TPR domains, responsible for protein protein interactions with heat shock proteins HSP90 and HSP70, and N-terminal domains with peptidyl-prolyl isomerase activity [1]. Our previous results showed that FKBP51 positively regulates the expression of TGF-β, in melanoma [4]. We hypothesized a role for FKBP51 in potentiating the tumour promoting activities of TGF-β, in melanoma
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