Cancer Associated Fibroblasts

There is currently no effective treatment for pancreatic ductal adenocarcinoma (PDAC). While palliative chemotherapy offers a survival benefit to most patients, nearly all will eventually progress on treatment and long-term survivability remains poor. Given the lack of subsequent line treatment options for PDAC, immunotherapy has long been under exploration in PDAC, particularly given the resounding success of immune checkpoint inhibitors in other cancers. However, progress in immunotherapy against PDAC has been exceptionally difficult. Though many such approaches have been explored in clinical trials, few have shown significant therapeutic efficacy (summarized in Principe et al., Cancer Letters 2021). Our group has been particularly interested in the cellular mechanisms underlying the clinical failure of immunotherapy in PDAC, with the ultimate goal of developing novel combination strategies to improve therapeutic responses and long-term survival. Through these efforts, we have identified select populations of cancer-associated fibroblasts (CAFs) that facilitate immune evasion in PDAC, thereby limiting therapeutic responses to cancer immunotherapy. In the corresponding image, we show patient-derived CAFs cultured routinely in our laboratory to study these events. Cells were stained with DAPI (blue) to label cell nuclei, as well as for α-Smooth Muscle Actin (red) to affirm their myofibroblast-like phenotype, and Tubulin (green) to show the overall cell architecture. By using these in vitro systems in parallel with mouse models, ex vivo slice cultures, and human PDAC specimens, we have identified several potential means of disrupting CAF-mediated immune suppression (Principe et al., PNAS 2022, Cancer Research 2020, & Molecular Cancer Therapeutics 2019), one of which is now showing early promise in Phase 1 clinical testing. As these studies advance to the next stages of clinical testing, our lab is continuing work to identify alternate combination strategies to further improve therapeutic responses for what is largely considered an untreatable disease.