IRAK4 Signaling Drives Resistance to Checkpoint Immunotherapy in Pancreatic Ductal Adenocarcinoma

Targeting IRAK4 Signaling in PDAC: Turning the “Cold” Tumors to “Hot” Ones

“…In summary, this study by Somani et al 7 demonstrates that IRAK4-mediated NF-kB activation contributes to T cell exhaustion in PDAC TME (Figure 1) through expression of suppressive cytokines, checkpoint ligands, and HAS2. Moreover, pharmacologic inhibition of IRAK4 suppresses the expression of these molecules and increases T cell infiltration, thereby making PDAC tumors vulnerable to checkpoint immunotherapy (Figure 1).…”

“…In this study, the investigators have used gene expression signatures to identify T cell exhaustion and show that the PDAC samples with high NF-kB activation correlate with high T cell exhaustion signature in The Cancer Genome Atlas database. 7 Furthermore, PDAC tumors with high RELA expression (a marker of NF-kB activation) showed lower pro-T cell CAF signatures, along with higher T cell exhaustion signatures, which was associated with poor progression-free survival in patients with PDAC. Intriguingly, high IRAK4 expression positively correlates with T cell exhaustion in patients with PDAC.…”

“…6 However, to date, the involvement of IRAK4 signaling in mediating the immunosuppression in PDAC has not been investigated. The study conducted by Somani et al, 7 published in the current issue of Gastroenterology, is a timely investigation into the role of IRAK4-mediated NF-kB activation in causing immunosuppressive TME in pancreatic cancer.…”

“…In the current issue, the authors have shown that the IRAK4-mediated expression of HAS2 regulates intratumoral HA content in PDAC to impair T cell response. 7 Lastly, the investigators tested the therapeutic efficacy of CA4948, an IRAK4 inhibitor, alone or in combination with chemotherapy or immunotherapy, and observed encouraging results, as shown by the prolonged survival of KPC mice. 7 Despite these accomplishments, one obvious limitation of the present study was the failure to address the effect of IRAK4 inhibition in PDAC metastasis.…”

Proteolysis Targeting Chimeric Molecules: Tuning Molecular Strategies for a Clinically Sound Listening

“…IRAK4 is involved in innate immunity signaling, activated by toll-like receptors and interleukin 1-receptor IL-1Rs, through the formation of a multiprotein complex called myddosome [ 36 ]. The role of IRAK4 in the assembly of the myddosome relies on both its kinase activity and its scaffolding function, the former involved in the downstream events of the IRAK4–JNK axis, the latter involved in NF-κB activation [ 37 ]. On this base, the development of an IRAK4 degradation enhancer was thought to allow the simultaneous blocking of both kinase activity and the scaffolding functions [ 38 ].…”