Abstract
Pancreatic adenocarcinoma (PDA) is one of the most lethal cancers, primarily due to late diagnosis. PDA is a highly stromal (desmoplastic) and poorly vascularized tumor with a dense extracellular matrix; only ~10% of the cells in the tumor are tumor cells, with the rest of the tumor microenvironment (TME) being comprised of cancer-associated fibroblasts (CAFs, and immune cells, including tumor-associated macrophages (TAMs). To investigate the role of cellular crosstalk between CAFs and tumor cells TME, we set out to identify paracrine factors secreted by activated CAFs in the tumor tissue that act on the tumor cells and can be targeted for therapeutic purposes. Through these studies, we identified the LIF (leukemia inhibitory factor) cytokine, secreted by activated CAFs, that acts on tumor cells to promote survival and maintain stemness, thereby serving as a driver of PDA progression. We have shown that therapeutic targeting of LIF by a neutralizing anti-LIF monoclonal antibody in the G12VKRas/Δp53KPC mouse model of PDA prolongs survival and increases sensitivity to chemotherapy, implicating LIF signaling as a therapeutic resistance mechanism. We found that LIF levels are elevated in human PDA tissue, and that high LIF levels correlate with disease progression. Serum LIF levels are also elevated in PDA patients and correlate with disease stage, suggesting that LIF could be a useful PDA biomarker, as well as a target for combination PDA therapy. Phase 2 PDA clinical trials with a humanized neutralizing anti-LIF mAb in combination with an anti-PD-L1 mAb are underway.
Recently, we have shown that an HDAC inhibitor in combination with gemcitabine slows the growth of KPC tumors by acting on the CAFs to block desmoplastic signals, and also to reduce expression of LIF. We have also found that LIF contributes to PDA tumor cell resistance to T cell killing, and that mAb neutralization of LIF can enhance the PDA tumor cell killing activity of an engineered T cell line. We are currently exploring the role of oncostatin M (OSM), a cytokine related to LIF that is predominantly made by TAMs, in intercellular crosstalk in PDA and tumor progression, to determine if OSM could be another PDA drug target.
