Immune checkpoint blockade therapy (ICBT), which blocks negative immune-activating signals and maintains the antitumor response, has elicited a remarkable clinical response in certain cancer patients. However, intrinsic resistance (i.e., insensitivity of the tumors to therapy) remains a daunting challenge. The efficacy of ICBT is tightly modulated by the function of each step in the antitumor immunity cycle. Mechanistically, the number of mutations determines tumor immunogenicity. The properties of the tumor microenvironment control T-cell infiltration, distribution, and function in tumor tissues. Low tumor immunogenicity and a strong immunosuppressive tumor microenvironment cause significant intrinsic resistance to ICBT. With our evolving understanding of intrinsic resistance, people have successfully tested, in preclinical models, treatments targeting specific resistance mechanisms to sensitize ICBT-resistant tumors. Translation of those preclinical findings to the clinical arena will help generate personalized ICBT strategies that target tumor-specific resistance mechanisms. Progress in the new personalized ICBT strategies will expand the reach of immunotherapy to more cancer types, thus enabling more patients to benefit. .

Existing preclinical models of human colorectal cancer (CRC) that rely on syngeneic subcutaneous grafts are problematic, because of increasing evidence that the immune microenvironment in subcutaneous tissue is significantly different from the gastrointestinal tract. Similarly, existing orthotopic models that use a laparotomy for establishing grafts are also problematic, because the surgical procedure results in extensive inflammation, thereby creating a nonphysiologic tumor microenvironment. To facilitate the bench-to-bedside translation of CRC immunotherapy strategies, we developed a novel orthotopic model in mice that uses endoscopy-guided microinjection of syngeneic cancer cells. When we compared immune system infiltration, we found that tumors in the subcutaneous model had fewer T cells, B cells, and natural killer (NK) cells, but more immunosuppressive myeloid cells; in contrast, tumors in our orthotopic model had a higher number of tumor-infiltrating T cells, B cells, and NK cells, with fewer immunosuppressive myeloid cells. The number of immune-stimulating cytokines, such as interleukin (IL)-2, IL-6, interferon (IFN)-gamma, and granzyme B, was also higher in tumors in our model, as compared with the subcutaneous model. Those differences resulted in heightened sensitivity to immune checkpoint blockade therapy in our endoscopy-guided orthotopic CRC model. Our study indicates that tumor location affects immune response in CRC mouse models; choosing the appropriate preclinical model is important when testing immunotherapy in CRC.

Purpose Pancreatic cancer stromal microenvironment is considered to be the major reason for failure of conventional and targeted therapy for this disease. The desmoplastic stroma, comprising mainly of collagen and glycosaminoglycans like hyaluronan (HA), is responsible for compression of vasculature in the tumor resulting in impaired drug delivery and poor prognosis. Minnelide, a water-soluble pro-drug of triptolide currently in Phase I clinical trial, has been very effective in multiple animal models of pancreatic cancer. However, whether Minnelide will have efficacious delivery into the tumor in spite of the desmoplastic stroma, has not been evaluated before. Experiment design Patient tumor derived xenografts (PDX) and spontaneous pancreatic cancer mice were treated with 0.42 mg/kg and 0.21 mg/kg body weight for 30 days. Stromal components were determined by IHC and ELISA based assays. Vascular functionality and drug delivery to the tumor were assessed following treatment with Minnelide. Result Our current study shows that treatment with Minnelide resulted in reduction of ECM components like hyaluronan (HA) and collagen in the pancreatic cancer stroma of both the spontaneous KPC mice as well as in patient tumor xenografts. Further, treatment with Minnelide improved functional vasculature in the tumors resulting in 4- times more functional vessels in the treated animals compared to untreated animals. Consistent with this observation, Minnelide also resulted in increased drug delivery into the tumor compared to untreated animals. Along with this, Minnelide also decreased viability of the stromal cells along with the tumor cells in pancreatic adenocarcinoma. Conclusion In conclusion, these results are extremely promising as they indicate that Minnelide, along with having anti-cancer effects is also able to deplete stroma in pancreatic tumors, which makes it an effective therapy for pancreatic cancer.

Resident fibroblasts that contact tumor epithelial cells (TEC) can become irreversibly activated as cancer-associated-fibroblasts (CAF) which stimulate oncogenic signaling in TEC. In this study, we evaluated the crosstalk between CAF and TEC isolated from tumors generated in a mouse model of KRAS/mutp53-induced pancreatic cancer (KPC mice). Transcriptomic profiling conducted after treatment with the anticancer compound Minnelide revealed deregulation of the TGF-β signaling pathway in CAF, resulting in an apparent reversal of their activated state to a quiescent, non-proliferative state. TEC exposed to media conditioned by drug-treated CAF exhibited a decrease in oncogenic signaling as manifested by downregulation of the transcription factor Sp1. This inhibition was rescued by treating TEC with TGF-β. Given promising early clinical studies with Minnelide, our findings suggest that approaches to inactivate CAF and prevent tumor-stroma crosstalk may offer a viable strategy to treat pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most