Opening the window for immunotherapy in pancreatic cancer

Abstract KRAS inhibitors (KRASi) are reshaping the treatment of aggressive tumors such as pancreatic ductal adenocarcinoma (PDAC), but it is appreciated that patients will eventually acquire resistance through multiple pathways. To avoid this outcome, there is much effort to identify combination therapies that take advantage of the ‘window-of-opportunity’ permitted from KRAS inhibition. Tumor cell-intrinsic targeting – as a result of KRASi – results in altered immune and stromal features within the PDAC tumor site that could allow for improved, non-KRAS-targeted, treatment efficacy. Qiang and colleagues investigate the potential of pairing KRASi with immunotherapy – here, an IL-21 mimic – for therapeutic benefit during this ‘open window’ phase of the KRASi-induced tumor debulking. IL-21 promotes a CD4 T cell response that requires both conventional type 2 dendritic cells (cDC2s) and interferon (IFN)-γ, but not direct tumor cell recognition via major histocompatibility complex (MHC). This work fits in a series of studies highlighting the ability to drive PDAC tumor rejection through cytokines derived from CD4, but not CD8, T cells. These findings highlight a divergence from more ‘traditional’ immunotherapeutic responses, where cytotoxic CD8 T cells have historically dominated tumor control. Identifying alternative paths towards targeting PDAC may be beneficial – and points towards cell types and modalities that could be leveraged for clinical benefit as the field identifies potential combinatorial partners for KRASi and more patients start receiving these drugs.