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.,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.,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.,FKBP51s may guide in the selection and monitoring of melanoma patient candidates to immune-checkpoint-targeted therapy.,Manipulation of FKBP51s may overcome resistance.
Genetically engineered T cells expressing a T-cell receptor (TCR) are powerful tools for cancer treatment and have shown significant clinical effects in sarcoma patients.,However, mismatch of the introduced TCR α/β chains with endogenous TCR may impair the expression of transduced TCR, resulting in an insufficient antitumor capacity of modified T cells.,Here, we report the development of immunotherapy using human lymphocytes transduced with a codon-optimized melanoma-associated antigen (MAGE)-A4 and HLA-A*2402-restricted TCR, which specifically downregulate endogenous TCR by small interfering RNA (si-TCR).,We evaluated the efficacy of this immunotherapy in both NOD-SCID mice and uterine leiomyosarcoma patients.,Our results revealed that transduced human lymphocytes exhibited high surface expression of the introduced tumor-specific TCR, enhanced cytotoxic activity against antigen-expressing tumor cells, and increased interferon-γ production by specific MAGE-A4 peptide stimulation.,Retarded tumor growth was also observed in NOD-SCID mice inoculated with human tumor cell lines expressing both MAGE-A4 and HLA-A*2402.,Furthermore, we report the successful management of a case of uterine leiomyosarcoma treated with MAGE-A4 si-TCR/HLA-A*2402 gene-modified T cells.,Our results indicate that the TCR-modified T cell therapy is a promising novel strategy for cancer treatment.