Neogambogic acid enhances anti-PD-1 immunotherapy efficacy by attenuating suppressive function of MDSCs in pancreatic cancer.

BACKGROUND: Anti-PD-1-based immunotherapy has limited benefits in patients with pancreatic cancer. Accumulating data indicate that natural products exert antitumor activity by remodeling the tumor immune microenvironment. It has been reported that neogambogic acid (NGA), an active natural monomer extracted from Garcinia, has anti-inflammatory and antitumor effects. Nevertheless, there are few systematic studies on the antitumor efficacy and immunomodulatory effects of NGA in pancreatic cancer. METHODS: An orthotopic mouse model of pancreatic cancer was established and were treated with different doses of NGA. Tumor growth and ascites were observed. Flow cytometry and immunohistochemistry (IHC) were used to investigate the tumor immune microenvironment. CD11b+ MDSCs were infused back into mice with pancreatic cancer to observe tumor progression after NGA treatment. Bone marrow cells were induced to differentiate into MDSCs, and the effects of NGA on MDSCs were analyzed and the underlying mechanism was explored. The effects of NGA combined with an anti-PD-1 antibody on pancreatic cancer were further tested. RESULTS: NGA significantly inhibited the tumor growth and improve ascites character in pancreatic cancer model mice. Flow cytometry and IHC analysis revealed that NGA decreased the MDSCs proportion and infiltration in the tumor microenvironment. Moreover, adoptive MDSCs largely attenuated the inhibitory effect of NGA on the progression of pancreatic cancer. In addition, we showed that NGA significantly promoted apoptosis and inhibited the differentiation, migration and immunosuppressive function of MDSCs and decreased level of STAT3 and p-STAT3. Furthermore, we demonstrated that NGA synergistically enhanced the efficacy of anti-PD-1 antibodies against pancreatic cancer. CONCLUSION: NGA inhibited the progression of pancreatic cancer by inhibiting MDSCs in the tumor microenvironment, and enhanced the efficacy of anti-PD-1 therapy in the treatment of pancreatic cancer.

Hydroxygenkwanin suppresses peritoneal metastasis in colorectal cancer by modulating tumor-associated macrophages polarization.

Peritoneal metastasis is an important cause of high mortality and poor prognosis in colorectal cancer (CRC) patients. Therefore, the development of compounds with unique anti-CRC Peritoneal metastasis activities is urgently needed to improve the survival of CRC patients. Hydroxygenkwanin (HGK),a natural flavonoid compound, have been shown to display anti-inflammatory, antioxidant, antitumor, and immunoregulatory effects. Here, we employed CRC peritoneal metastasis mouse model with MC38 cells to examine the antitumor activity of HGK. The result showed that HGK not only inhibited peritoneal metastasis, but also significantly increased the proportion of M1-like macrophages while decreasing the proportion of M2-like macrophages within the tumor microenvironment (TME). Furthermore, we demonstrated that the inhibitory effect of HGK on peritoneal metastasis of CRC depended on macrophages in vitro and in vivo. Moreover, we revealed that HGK promoted the polarization of TAMs into M1-like macrophages and inhibited their polarization into M2-like macrophages in a LPS- or IL-4-induced bone marrow-derived macrophages (BMDMs) model and co-culture system. Finally, we also investigated the regulatory mechanism of HGK on TAMs polarization that HGK may active p-STAT5, p-NF-κB signaling in M1-like macrophages and inhibit p-STAT6, JMJD3, PPARγ expression in M2-like macrophages. Taken together, our findings suggest that HGK is a natural candidate for effective prevention of peritoneal metastasis in colorectal cancer, which provides a potential strategy for clinical treatment of colorectal cancer.

Incidence and risk factors for second malignancies among patients with myeloproliferative neoplasms.

OBJECTIVE: The clinical characteristics and survival of patients with myeloproliferative neoplasms (MPNs) with secondary cancer were analyzed to explore the possible risk factors for secondary cancer in MPN patients. METHODS: The clinical characteristics of 1060 Chinese patients with MPN were retrospectively analyzed. The Kaplan-Meier method was used to analyze the survival. The Cox multivariate regression model was used to analyze the risk factors for developing secondary cancer in patients with MPNs. RESULTS: The 1060 patients with MPN had a median follow-up of 10 years (range 1-50) and a median age of 55 years (range 21-86), and 497 (45.2%) were male. The proportion of PV, ET, and PMF was 52.2%, 33.5%, and 14.3%, respectively. About 28.1% (298/1060) of 1060 MPN patients died. The median survival times of the PV, ET, and PMF groups were 20, 24, and 12 years, respectively (p < 0.0001). In age- and sex-matched healthy Chinese patients, the standardized incidence ratio (SIR) value of developing secondary cancer in MPN patients was 6.41 (95% CI: 4.90-9.48). The median survival time was 14 years in the MPN with secondary cancer group. The Cox multivariate analysis showed that age ≥ 65 years (p < 0.0001, HR = 5.027, 95% CI [2.823, 8.952]), MF-1 (p = 0.001, HR = 2.887, 95% CI [1.503, 5.545]) were risk factors for developing secondary cancer. CONCLUSIONS: The survival of MPN patients with secondary cancer was significantly worse than that of patients without secondary cancer. Compared with normal subjects, MPN patients had a 6.41-fold increased risk of developing secondary cancer, and age ≥ 65 years and MF-1 were risk factors for developing secondary cancer in MPN patients.

Thrombosis in patients with post-polycythemia vera myelofibrosis: incidence and risk factors.

INTRODUCTION: Post-polycythemia vera (PV) myelofibrosis (Post-PV MF) is an advanced phase of natural progression of PV. Thrombosis is a major cause of morbidity and mortality in PV; however, the characteristics of thrombosis in post-PV MF have not been characterised. METHODS: The clinical and laboratory characteristics of 163 patients with post-PV MF were analysed. Kaplan-Meier and multivariate Cox analyses were used to estimate risk factors for thrombosis. RESULTS: During follow-up, 84 (51.5%) patients developed thrombosis, 11 (6.7%) progressed to acute leukemia, 35 (21.5%) died (20% due to thrombosis). Thrombosis-free survival (TFS) in post-PV MF was lower than that of sex- and age-matched patients with PV (P < 0.0001). The incidence of venous thrombosis was significantly higher after diagnosis of post-PV MF than before or at diagnosis; Those with V617F% ≥ 75% or absolute monocyte count (AMC) ≥1.5 × 109/L demonstrated a higher risk for venous thrombosis (P < 0.05). According to multivariate Cox regression, palpable splenomegaly (hazard ratio [HR] 3.284 [95% confidence interval (CI) 1.373-7.855]; P = 0.008), age ≥ 60 years (HR 1.604 [95%CI 1.004-2.56]; P = 0.048), history of thrombosis (HR 2.767 [95%CI 1.735-4.412]; P < 0.001) were risk factors for thrombosis. In multivariable models, median TFS in post-PV MF in extremely high -, high -, intermediate -, low-risk groups were 2, 4, 9 and 13 years, respectively. CONCLUSION: Patients with post-PV MF demonstrated a higher incidence of thrombosis. Palpable splenomegaly, age ≥ 60 years, history of thrombosis were independent risk factors for thrombosis.