(A) Fine tuning of the T effector (Teff) response against AML though “activating” (OX40, ICOS, GITR, 4-1–BBL) and “exhausting” (PD-1/L1 CTLA4, TIM3, LAG3) checkpoint receptor-ligand pairs; (B) Increasing numbers of T regulatory cells (Tregs) with AML relapses leads to an increased immunosuppression and AML tolerance; (C) mutated TP53 leads to decreased transcription of microRNA-34 (miR-34) and subsequent transcriptional disinhibition of its target gene PD-L1 thus increasing expression of PD-L1 on AML blasts; increased numbers of Tregs and highly exhausted Teffs in AML impedes antitumor responses but may be amenable to PD-1/L1 axis antagonism by PD-1 inhibitors pembrolizumab/nivolumab or PD-L1 antagonist Atezolizumab; OX40 agonists may enhance tumor killing directly through CD8+ cytotoxic T cells (CTL) or indirectly through enhanced CD4+ Teff-mediated help.

(A) Fine tuning of the T effector (Teff) response against AML though “activating” (OX40, ICOS, GITR, 4-1–BBL) and “exhausting” (PD-1/L1 CTLA4, TIM3, LAG3) checkpoint receptor-ligand pairs; (B) Increasing numbers of T regulatory cells (Tregs) with AML relapses leads to an increased immunosuppression and AML tolerance; (C) mutated TP53 leads to decreased transcription of microRNA-34 (miR-34) and subsequent transcriptional disinhibition of its target gene PD-L1 thus increasing expression of PD-L1 on AML blasts; increased numbers of Tregs and highly exhausted Teffs in AML impedes antitumor responses but may be amenable to PD-1/L1 axis antagonism by PD-1 inhibitors pembrolizumab/nivolumab or PD-L1 antagonist Atezolizumab; OX40 agonists may enhance tumor killing directly through CD8+ cytotoxic T cells (CTL) or indirectly through enhanced CD4+ Teff-mediated help.

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