An immunophenotype approach identified an unknown Treg subset in PBMC of melanoma patients, as associated with response to anti-CTLA4

Recently, our group demonstrated that the inhibitory immune checkpoint PD-L1/PD1 promoted the alternative splicing of FKBP5 gene, resulting in increased expression of its variant 4, in PBMC of melanoma patients. Such variant 4 is translated into a truncated protein, termed FKBP51s. Based on the relevant role for co-inhibitory signaling in tumor immune escape, we thought to measure the expression of such a molecular sensor of PD-L1/PD1 interaction in melanoma patients, by PBMC immunophenotyping. The study was conducted on a cohort of 118 patients and 77 age- and sex-matched healthy controls. Blood samples were collected before patients underwent ipilimumab treatment. In 64 out of 118 patients, expression of FKBP51s was also assessed in regulatory T cells. Our findings showed that, physiologically, each PBMC subset analyzed contained an FKBP51spos fraction, which resulted expanded in melanoma patients. CD4 T lymphocytes showed the FKBP51sneg subset significantly impaired. Treg count was increased, in accordance with previous studies. The study of FKBP51sposTregs allowed to identify a subgroup of nonresponder patients to ipilimumab (p=0.002). In conclusion, FKBP51s-based immunophenotype of melanoma patients revealed several profiles virtually related to a negative immune regulatory control and disclosed an unknown Treg subset potentially useful in the selection of patients candidate to immunotherapy.