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. .

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.

AimsAltered expression of epithelial or stromal caveolin-1 (Cav-1) is observed in various types of human cancers. However, the clinical significance of Cav-1 expression in gastric cancer (GC) remains largely unknown. The present study aims to explore the clinicopathological significance and prognostic value of both tumor cells and cancer associated fibroblasts (CAFs) Cav-1 in GC.Methods and ResultsQuantum dots immunofluorescence histochemistry was performed to examine the expression of Cav-1 in 20 cases of gastritis without intestinal metaplasia (IM), 20 cases of gastritis with IM and 286 cases of GC. Positive rates of epithelial Cav-1 in gastritis without IM, gastritis with IM and GC showed a decreasing trend (P = 0.012). Low expression of Cav-1 in CAFs but not in tumor cells was an independent predictor of poor prognosis in GC patients (P = 0.034 and 0.005 respectively in disease free survival and overall survival). Cav-1 level in tumor cells and CAFs showed no significant correlation with classic clinicopathological features.ConclusionsLoss of epithelial Cav-1 may promote malignant progression and low CAFs Cav-1 level herald worse outcome of GC patient, suggesting CAFs Cav-1 may be a candidate therapeutic target and a useful prognostic marker of GC.

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.

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.

Use of the autophagy-related markers beclin-1 (BECN1) and microtubule-associated protein light chain 3B (LC3B) as prognostic markers has been extensively investigated in various kinds of cancers. However, their prognostic roles are still controversial and not firmly validated. We systematically reviewed the evidence from various studies concerning the relationship between BECN1 and LC3B expression in cancers and overall survival (OS)/disease-free survival (DFS) to elucidate this issue. PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI) were searched in July 2013 (then updated in April 2014) to identify eligible cohort studies that reported associations between BECN1 or LC3B expression and OS/DFS in cancer patients. Combined hazard ratios (HRs) with 95 % confidence intervals (95 % CIs) were pooled using fixed-effects or random-effects models according to heterogeneity in different groups. A total of 23 studies in distinct cancers were eligible for systematic review and meta-analysis. Our pooled results identified that a high expression of BECN1 is associated with favorable OS in gastric cancer (HR = 0.49, 95 % CI = 0.34-0.72) and lymphoma (HR = 0.25, 95 % CI = 0.11-0.57), whereas a high expression of LC3B predicts adverse OS in breast cancer (HR = 1.98, 95 % CI = 1.25-3.13). This systematic review and meta-analysis indicated that the autophagy-related marker BECN1 might be a predictive factor of favorable prognosis in gastric cancer, breast cancer, and lymphoma and LC3B might predict unfavorable prognosis of breast cancer. Nevertheless, due to the limited number and retrospective design of the original studies, more powerful prospective cohorts are required to verify these conclusions.

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

Caveolin-1 (Cav-1), a major structural protein of caveolae, is an integral membrane protein which plays an important role in the progression of carcinoma. However, whether Cav-1 acts as a tumor promoter or a tumor suppressor still remains controversial. For example, the tumor-promoting function of Cav-1 has been found in renal cancer, prostate cancer, tongue squamous cell carcinoma (SCC), lung SCC and bladder SCC. In contrast, Cav-1 also plays an inhibitory role in esophagus adenocarcinoma, lung adenocarcinoma and cutaneous SCC. The role of Cav-1 is still controversial in thyroid cancer, hepatocellular carcinoma, gastric adenocarcinoma, colon adenocarcinoma, breast cancer, pancreas cancer, oral SCC, laryngeal SCC, head and neck SCC, esophageal SCC and cervical SCC. Besides, it has been reported that the loss of stromal Cav-1 might predict poor prognosis in breast cancer, gastric cancer, pancreas cancer, prostate cancer, oral SCC and esophageal SCC. However, the accumulation of stromal Cav-1 has been found to be promoted by the progression of tongue SCC. Taken together, Cav-1 seems playing a different role in different cancer subtypes even of the same organ, as well as acting differently in the same cancer subtype of different organs. Thus, we hereby explore the functions of Cav-1 in human adenocarcinoma and SCC from the perspective of clinical significances and pathogenesis. We envision that novel targets may come with the further investigation of Cav-1 in carcinogenesis.