Table 3.
Selected preclinical studies investigating other resistance mechanisms
| Study | Study design | Findings |
|---|---|---|
| Zaretsky et al.78 | Paired liquid and tissue biopsies from baseline and after progression in four patients who progressed following initial response to pembrolizumab were molecularly characterised | A truncating β2-microglobulin and loss of function mutations in JAK1/2 with concurrent loss of wild-type allele were identified. |
| Zhao et al.76 | Molecular characterisation was performed in tissue samples of a melanoma patient which were obtained throughout multiple recurrences over 6 years | Loss of HLA class I expression in melanoma clones was identified in late recurrent disease leading to T-cell resistance |
| Spranger et al.58 | Comparative gene expression profiling was performed in 266 metastatic melanoma patients. | Activated Wnt/β-catenin signalling reduces CD8+ T- cell infiltration into tumour microenvironment leading to resistance to anti-PD-1 and Anti-CTLA-4 therapy. |
| Yaguchi et al.59 | Mechanistic study in a murine model of melanoma cell lines (B16 and K1735) | Increased Wnt signalling reduces IFN-γ levels leading to progressive immune resistance to which was reversed by a β-catenin inhibitor (PKF115-584) |
| Chen et al.64 | Peripheral CD4+CD25− naive T cells were treated with TGF-β in vivo and in vitro | TGF-β enhanced Foxp3 gene expression in TCR-challenged CD4+CD25− naive T cells, which led to transition toward regulatory T cells which were carrying highly immunosuppressive potential |
| Marie et al.66 | C57BL/6 (B6) and TCRβ/δ-deficient mice were examined for peripheral T regulatory cells quantification | TGF-β1-deficient mice demonstrated peripheral, but not thymic, T regulatory cells. TGF-β1 functions in T regulatory maintenance |
| Thomas et al.68 | The effect of TGF-β was investigated in EL4 thymoma cells using a mouse model. | TGF-β suppresses effector function of T cells by actively downregulating the expression of perforin, granzyme A/B and Fas ligand, and thereby leading immune evasion and resistance |
TGF-β Transforming growth factor- β, TCRβ T-cell receptor β chain, IFN-γ Interferon- γ, JAK1/2 Janus kinase 1/2, anti-PD-1 Programmed cell death protein 1, anti-CTLA4 Cytotoxic T-lymphocyte-associated antigen