Abstract
BackgroundFKBP51 immunophilin is abundantly expressed by immune cells. Co-inhibitory immune receptor signalling generates the splicing isoform FKBP51s. Tregs stained by FKBP51s are increased in melanoma patients and their counts are associated with anti-CTLA-4 response. An expansion of FKBP51s+PD-L1+ monocytes was measured in a group of non-responding patients to anti-CTLA-4. The aim of this work was to confirm the predictive value of response of FKBP51s+Tregs in a cohort of patients undergoing anti-PD1 treatment and shed light on a monocyte subset co-expressing PD-L1/FKBP51s.MethodsCo-cultures of organoids and autologous lymphocytes were used to confirm that tumour T-cell interaction can induce FKBP51s. PBMC immunophenotype and flow cytometry served to assess and monitor FKBP51s+Treg and FKBP51s+PD-L1+ monocytes in 22 advanced melanoma patients treated with anti-PD1. Silencing and overexpression of FKBP51s in human macrophages served to address the protein role in the tolerant macrophages’ behaviour.ResultsFKBP51s+Tregs count was increased in responders and had a prognostic value. Non-responders showed an early increase in FKBP51s+ PD-L1+ monocytes during anti-PD1 treatment. Manipulation of FKBP51s modulated the macrophage–phenotype, with forced protein expression promoting aspects associated with tolerance.ConclusionsFKBP51s may guide in the selection and monitoring of melanoma patient candidates to immune-checkpoint-targeted therapy. Manipulation of FKBP51s may overcome resistance.
Highlights
FKBP51 immunophilin is abundantly expressed by immune cells
Organoids generated from melanoma tumours can affect FKBP51s expression in co-cultured autologous peripheral blood mononuclear cell (PBMC) We have previously shown that tumour-immune cell interaction through PD-L1/PD1 bidirectionally stimulated FKBP5 alternative splicing.[7,17]
We have shown that expression of FKBP51s in tumour-infiltrating lymphocytes of melanoma tissues is influenced by tumour PD-L1 expression.[7]
Summary
FKBP51 immunophilin is abundantly expressed by immune cells. Co-inhibitory immune receptor signalling generates the splicing isoform FKBP51s. Tregs stained by FKBP51s are increased in melanoma patients and their counts are associated with anti-CTLA-4 response. The aim of this work was to confirm the predictive value of response of FKBP51s+Tregs in a cohort of patients undergoing anti-PD1 treatment and shed light on a monocyte subset co-expressing PD-L1/FKBP51s. PBMC immunophenotype and flow cytometry served to assess and monitor FKBP51s+Treg and FKBP51s+PD-L1+ monocytes in 22 advanced melanoma patients treated with anti-PD1. Approved medications include anti-PD1 (nivolumab and pembrolizumab), anti-CTLA-4 (ipilimumab) and anti-PD1/-CTLA-4 combination Overall, these regimens work to induce reactivation of tumour-specific antigen-experienced T cells that destroy the tumour.[1,2] Notwithstanding the dramatic outcomes of such an immunotherapeutic approach, high rates of clinically significant immune-related adverse events, especially with dual- combination regimens, occur that are often associated with no/poor response.
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