BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors owing to its robust desmoplasia, low immunogenicity, and recruitment of cancer-conditioned, immunoregulatory myeloid cells. These features strongly limit the success of immunotherapy as a single agent, thereby suggesting the need for the development of a multitargeted approach. The goal is to foster T lymphocyte infiltration within the tumor landscape and neutralize cancer-triggered immune suppression, to enhance the therapeutic effectiveness of immune-based treatments, such as anticancer adoptive cell therapy (ACT).MethodsWe examined the contribution of immunosuppressive myeloid cells expressing arginase 1 and nitric oxide synthase 2 in building up a reactive nitrogen species (RNS)-dependent chemical barrier and shaping the PDAC immune landscape. We examined the impact of pharmacological RNS interference on overcoming the recruitment and immunosuppressive activity of tumor-expanded myeloid cells, which render pancreatic cancers resistant to immunotherapy.ResultsPDAC progression is marked by a stepwise infiltration of myeloid cells, which enforces a highly immunosuppressive microenvironment through the uncontrolled metabolism of L-arginine by arginase 1 and inducible nitric oxide synthase activity, resulting in the production of large amounts of reactive oxygen and nitrogen species. The extensive accumulation of myeloid suppressing cells and nitrated tyrosines (nitrotyrosine, N-Ty) establishes an RNS-dependent chemical barrier that impairs tumor infiltration by T lymphocytes and restricts the efficacy of adoptive immunotherapy. A pharmacological treatment with AT38 ([3-(aminocarbonyl)furoxan-4-yl]methyl salicylate) reprograms the tumor microenvironment from protumoral to antitumoral, which supports T lymphocyte entrance within the tumor core and aids the efficacy of ACT with telomerase-specific cytotoxic T lymphocytes.ConclusionsTumor microenvironment reprogramming by ablating aberrant RNS production bypasses the current limits of immunotherapy in PDAC by overcoming immune resistance.

Pancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide. Identification of novel tumor biomarkers is highly advocated in PC to optimize personalized treatment algorithms. Blood-circulating extracellular vesicles hold promise for liquid biopsy application in cancer. We used an optimized flow cytometry protocol to study leukocyte-derived EVs (CD45+) and PD-L1+ EVs in blood from 56 pancreatic cancer patients and 48 healthy controls (HCs). Our results show that PC patients presented higher blood levels of total EVs (p = 0.0003), leukocyte-derived EVs (LEVs) (p = 0.001) and PD-L1+ EVs (p = 0.01), as compared with HCs. Interestingly, a blood concentration of LEVs at baseline was independently associated with improved overall survival in patients with borderline resectable or primary unresectable PC (HR = 0.17; 95% CI 0.04–0.79; p = 0.02). Additionally, increased blood-based LEVs were independently correlated with prolonged progression-free survival (HR = 0.10; 95% CI 0.01–0.82; p = 0.03) and significantly associated with higher disease control rate (p = 0.02) in patients with advanced PC receiving standard chemotherapy. Notably, a strong correlation between a decrease in blood LEVs concentration during chemotherapy and disease control was observed (p = 0.005). These intriguing findings point to the potential of LEVs as novel blood-based EV biomarkers for improved personalized medicine in patients affected by PC.

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Uterine sarcomas (USs) account for 3-9% of uterine malignant neoplasia and about 5% of all gynaecologic malignancies. Despite their low prevalence, these tumors stimulate a great interest because of their aggressiveness, poor prognosis and high mortality rate. According to the last world health organization (WHO) classification and the International Federation of gynecology and obstetrics committee (FIGO) staging, USs are categorized as pure mesenchymal tumors (endometrial stromal sarcoma, leiomyosarcoma and undifferentiated uterine) and mixed tumors (carcinosarcoma and adenosarcoma). Due to their non-specific signs and symptoms, USs are commonly diagnosed in advanced stage, more often after surgery for a suspected leiomyoma. Although surgery followed by adjuvant therapies represent the common choices for USs, they show poor efficacy due to the early occurrence of metastasis, and the high resistance of tumors to radio-and chemotherapy. Presently, specific expression profiles and new cytotoxic agents are under investigation. In these reviews, we summarized clinical and pathological features, imaging characteristics, therapeutic approaches, genomic and molecular aberration associated with smooth muscle neoplasia (Part 1) and endometrial stromal neoplasia (Part 2); the goal is to understand the biology and the molecular signature of these tumors, in order to focus on their best management.

Uterine sarcomas (USs) account for 3-9% of uterine malignant neoplasia and about 5% of all gynaecologic malignancies. Despite their low prevalence, these tumors stimulate a great interest because of their aggressiveness, poor prognosis and high mortality rate. According to the last World Health Organization (WHO) classification and the International Federation of Gynecology and Obstetrics Committee (FIGO) staging, USs are categorized as pure mesenchymal tumors (endometrial stromal sarcoma, leiomyosarcoma and undifferentiated uterine), and mixed tumors (carcinosarcoma and adenosarcoma). Due to their non-specific signs and symptoms, USs are commonly diagnosed in advanced stage, more often after surgery for a suspected leiomyoma. Although surgery followed by adjuvant therapies represent the common choices for USs, they show poor efficacy due to the early occurrence of metastasis, and the high resistance of tumors to radio-and chemotherapy. Presently, specific expression profiles and new cytotoxic agents are under investigation. In these reviews, we summarized clinical and pathological features, imaging characteristics, therapeutic approaches, genomic and molecular aberration associated with smooth muscle neoplasia (Part 1) and endometrial stromal neoplasia (Part 2); the goal is to understand the biology and the molecular signature of these tumors, in order to focus on their best management.