IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma

Abstract

Inflammation mediated by activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL-6 receptor (IL6R) as a strategy to inhibit IL-6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1Cre (KPC) mice. Plasma from patients with PDAC was assessed for its ability to activate STAT3/SOCS3 in human monocytes using immunofluorescence microscopy and quantitative gene expression assays. KPC mice and syngeneic mice (wild-type and IL6−/−) implanted with KPC-derived cell lines were treated with an IL6R blocking antibody (anti-IL6R). The impact of treatment on tumor growth in KPC mice and mice with KPC-derived tumor implants was monitored using ultrasonography and calipers, respectively. Tumors were analyzed by immunohistochemistry to detect changes in STAT activation, tumor viability and proliferation. We found that STAT3 was the most activated STAT protein in PDAC tumors from KPC mice. Plasma from patients with advanced PDAC stimulated STAT3/SOCS3 activation in human monocytes. In mice, anti-IL6R antibodies targeted Ly6Chi monocytes, inhibited STAT3 activation in tumor cells and decreased tumor cell proliferation in vivo. IL6R blockade in combination with chemotherapy induced tumor cell apoptosis, tumor regressions and improved overall survival. Overall, we show that IL-6 signaling drives STAT3 activation in tumor cells and mediates chemoresistance in PDAC. Thus, disrupting IL-6 signaling using anti-IL6R antibodies holds promise for improving chemotherapy efficacy in PDAC.

IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma

“…Among the reasons for PDAC lethality, late diagnosis and resistance to chemotherapy play a central role. Factors that contribute to this resistance include the presence of a poorly vascularized, extensive stroma that acts as a barrier to drug delivery (2)(3)(4)(5), and cytokines and growth factors secreted by nonneoplastic stromal cells that attenuate drug responses (6)(7)(8)(9)(10). Although numerous studies have focused on the genetic and epigenetic forces that drive PDAC progression, less is understood about the complex tumor microenvironment (TME).…”

Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis

“…We evaluated the circulating CD11b + Ly6C hi monocytic population in our assays, and AS+5-FU therapy induced a decreased percentage of CD11b + Ly6C hi circulating cells, indicating that STAT6 inhibition is a possible target for decreasing an immunological population that may favor resistance to 5-FU. Studies on pancreatic ductal adenocarcinoma indicated that decreased numbers of Ly6C hi monocytes may sensitize tumors to chemotherapy-induced cell death, given STAT6 activity is a requirement for the recruitment of inflammatory Ly6C hi monocytes and their conversion to tissue-remodeling M2 macrophages [59,60]; thus, the reduced expression of STAT6 phosphorylation could be responsible for the reduction of CD11b + Ly6C hi cells in our model. On the other hand, CD11b + Ly6C low Ly6G + granulocytic cells showed a decrease in the adjuvant therapies in the AS+5-FU group, in contrast to those levels detected in treatments such as individual therapies.…”

IL-6 Trans-Signaling and Crosstalk Among Tumor, Muscle and Fat Mediate Pancreatic Cancer Cachexia

“…Although circulating IL-6 levels are not always detectable in early PDAC nor always correlated with cachexia severity (Ramsey et al, 2019;Talbert et al, 2018), higher tumor staining for IL-6 is associated with PDAC cachexia (Martignoni et al, 2005) and induction of monocyte IL-6 is predictive of survival in PDAC (Moses et al, 2009), suggesting that the serum levels of this short-lived cytokine might not be an appropriate measure of tissue activity. Functional data also support a role for IL-6 in PDAC tumor development (Lesina et al, 2011), progression (Zhang et al, 2013), metastasis (Razidlo et al, 2018), anti-tumor immunity (Flint et al, 2016), and response to chemotherapy (Long et al, 2017). IL-6 levels are high in PDAC models with weight loss (Flint et al, 2016) and IL-6 is functionally linked to cachexia in murine C26 colon adenocarcinoma and other models of cancer cachexia (Baltgalvis et al, 2008;Bonetto et al, 2012;Bonetto et al, 2011;Narsale and Carson, 2014).…”

“…The data provided here strongly support targeted inhibition of IL-6R to treat PDAC cachexia. Pre-clinical studies document improved response to chemotherapy in mice with pancreatic cancer treated with anti-IL6R antibodies (Long et al, 2017); whether those mice also demonstrated reduced cachexia was not reported. An ongoing trial of the IL6R inhibitor Tocilizumab with gemcitabine and nabpaclitaxel in patients with advanced and metastatic disease might provide important insights on this approach in PDAC (Chen et al, 2017).…”