Figure 2.
Immunotherapeutic and pharmacologic approaches to restore HLA class II expression and leukemia recognition after allo-HCT. The upper panel shows immunotherapeutic interventions based on IFN-γ, either directly administered or released by immune cells, to recover HLA class II expression via activation of IFN-responsive elements in alternative regulatory regions of CIITA. The recognition by donor T cells (in red) of minor histocompatibility antigens (MiHAs) and tumor antigens on leukemia cells (in violet) upon HLA class I presentation and of HLA class I/II restricted MiHAs on other patient tissues in the setting of GVHD can lead to IFN-γ release. Bispecifics and CAR T cells can have both direct antileukemic effects (redirecting T-cell responses) and indirect effects, which leads to release of IFN-γ and restoration of anti-HLA alloreactivity. The lower panel shows interventions aimed at restoring HLA expression by acting on epigenetic mechanisms that lead to HLA class II downregulation. Reduced accessibility of HLA class II and CIITA genes at the promoter level are mediated by different chromatin regulators, such as PRC2 and CtBP complex, which rely respectively on the methytransferases EZH2 and EHMT1/2 to catalyze the trimethylation Lys-27 (H3K27me3) of histone H3 and the monomethylation and dimethylation of Lys-9 (H3K9me1-2). Targeting the main components of the PRC2 complex, namely EZH2, EED, and JARID2 with the respective inhibitors tazemetostat, EED226, and JIB-04 and EHMT1/2 with UNC0638/A-366, can reinstate HLA class II and CIITA expression. In addition, although RREB1 knockout leads to the activation of both CIITA and HLA class II expression, FBXO11 loss can activate HLA class II genes with no changes in CIITA mRNA levels, thereby blocking CIITA polyubiquitination and proteasomal degradation. Finally, the inhibition of MDM2 ubiquitin ligase by HDM201 also has been shown to induce the upregulation of TRAIL1/2 and HLA class II genes on leukemia cells.

Immunotherapeutic and pharmacologic approaches to restore HLA class II expression and leukemia recognition after allo-HCT. The upper panel shows immunotherapeutic interventions based on IFN-γ, either directly administered or released by immune cells, to recover HLA class II expression via activation of IFN-responsive elements in alternative regulatory regions of CIITA. The recognition by donor T cells (in red) of minor histocompatibility antigens (MiHAs) and tumor antigens on leukemia cells (in violet) upon HLA class I presentation and of HLA class I/II restricted MiHAs on other patient tissues in the setting of GVHD can lead to IFN-γ release. Bispecifics and CAR T cells can have both direct antileukemic effects (redirecting T-cell responses) and indirect effects, which leads to release of IFN-γ and restoration of anti-HLA alloreactivity. The lower panel shows interventions aimed at restoring HLA expression by acting on epigenetic mechanisms that lead to HLA class II downregulation. Reduced accessibility of HLA class II and CIITA genes at the promoter level are mediated by different chromatin regulators, such as PRC2 and CtBP complex, which rely respectively on the methytransferases EZH2 and EHMT1/2 to catalyze the trimethylation Lys-27 (H3K27me3) of histone H3 and the monomethylation and dimethylation of Lys-9 (H3K9me1-2). Targeting the main components of the PRC2 complex, namely EZH2, EED, and JARID2 with the respective inhibitors tazemetostat, EED226, and JIB-04 and EHMT1/2 with UNC0638/A-366, can reinstate HLA class II and CIITA expression. In addition, although RREB1 knockout leads to the activation of both CIITA and HLA class II expression, FBXO11 loss can activate HLA class II genes with no changes in CIITA mRNA levels, thereby blocking CIITA polyubiquitination and proteasomal degradation. Finally, the inhibition of MDM2 ubiquitin ligase by HDM201 also has been shown to induce the upregulation of TRAIL1/2 and HLA class II genes on leukemia cells.

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