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

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.

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