Background: 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. 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. Methods: Co-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. Results: FKBP51s+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. Conclusions: FKBP51s may guide in the selection and monitoring of melanoma patient candidates to immune-checkpoint-targeted therapy. Manipulation of FKBP51s may overcome resistance.

Alternative macrophage polarisation associated with resistance to anti-PD1 blockade is possibly supported by the splicing of FKBP51 immunophilin in melanoma patients / Troiani, Teresa; Giunta, Emilio Francesco; Tufano, Martina; Vigorito, Vincenza; D'Arrigo, Paolo; Argenziano, Giuseppe; Ciardiello, Fortunato; Romano, MARIA FIAMMETTA; Romano, Simona. - In: BRITISH JOURNAL OF CANCER. - ISSN 0007-0920. - 122:12(2020), pp. 1782-1790. [10.1038/s41416-020-0840-8]

Alternative macrophage polarisation associated with resistance to anti-PD1 blockade is possibly supported by the splicing of FKBP51 immunophilin in melanoma patients

Martina, Tufano;Paolo, D'Arrigo;Maria Fiammetta, Romano
;
Simona, Romano.
2020

Abstract

Background: 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. 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. Methods: Co-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. Results: FKBP51s+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. Conclusions: FKBP51s may guide in the selection and monitoring of melanoma patient candidates to immune-checkpoint-targeted therapy. Manipulation of FKBP51s may overcome resistance.
2020
Alternative macrophage polarisation associated with resistance to anti-PD1 blockade is possibly supported by the splicing of FKBP51 immunophilin in melanoma patients / Troiani, Teresa; Giunta, Emilio Francesco; Tufano, Martina; Vigorito, Vincenza; D'Arrigo, Paolo; Argenziano, Giuseppe; Ciardiello, Fortunato; Romano, MARIA FIAMMETTA; Romano, Simona. - In: BRITISH JOURNAL OF CANCER. - ISSN 0007-0920. - 122:12(2020), pp. 1782-1790. [10.1038/s41416-020-0840-8]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/816331
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