Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited therapeutic options and poor prognosis, largely due to late diagnosis and a profoundly immunosuppressive tumour microenvironment. Although cytotoxic chemotherapy remains the mainstay of treatment, the contribution of innate immune components to therapeutic efficacy is not fully understood. Group 1 innate lymphoid cells (ILCs), including Natural Killer cells (NKCs), play a critical role in immune surveillance and tumour control; however, their role in modulating chemotherapy responses in PDAC has not been systematically investigated. To address this, we employed a syngeneic orthotopic PDAC model (using a KrasG12D/+; Trp53R172H/+; PDX1-Cre; Rosa26YFP tumour cell line into immunocompetent C57BL/6 mice). These animals were treated with standard-of-care chemotherapy (Gemcitabine/Paclitaxel) in the presence or absence of NKCs/ILC1s depletion mediated by anti-NK1.1 antibodies. Tumour progression was monitored by ultrasonographic growth kinetics and endpoint volumetric analysis. We observed that chemotherapy alone significantly suppressed tumour growth, but this effect was markedly blunted in NKCs/ILC1-depleted mice, which displayed accelerated tumour growth and increased final tumour volumes compared to chemotherapy-treated controls. These findings indicate that NKCs, and more broadly Group 1 ILCs, are indispensable mediators of chemotherapy efficacy in PDAC. Our data underscore the interplay between cytotoxic therapies and innate immune effectors in shaping tumour outcomes. Importantly, they suggest that therapeutic strategies preserving or augmenting Group 1 ILCs activity could enhance chemotherapy responses in PDAC. This work provides a rationale for combinatorial approaches integrating immune modulation with standard-of-care chemotherapy to improve treatment efficacy in PDAC, an otherwise refractory disease.
Georgiades et al. (Sun,) studied this question.