The Biological Relevance of NHERF1 Protein in Gynecological Tumors.

Gynecological cancer management remains challenging and a better understanding of molecular mechanisms that lead to carcinogenesis and development of these diseases is needed to improve the therapeutic approaches. The Na+/H+ exchanger regulatory factor 1 (NHERF1) is a scaffold protein that contains modular protein-interaction domains able to interact with molecules with an impact on carcinogenesis and cancer progression. During recent years, its involvement in gynecological cancers has been explored, suggesting that NHERF1 could be a potential biomarker for the development of new targeted therapies suitable to the management of these tumors. This comprehensive review provides an update on the recent study on NHERF1 activity and its pathological role in cervical and ovarian cancer, as well as on its probable involvement in the therapeutic landscape of these cancer types.

Downstream Signaling of Inflammasome Pathway Affects Patients' Outcome in the Context of Distinct Molecular Breast Cancer Subtypes.

Inflammasomes are protein complexes involved in the regulation of different biological conditions. Over the past few years, the role of NLRP3 in different tumor types has gained interest. In breast cancer (BC), NLRP3 has been associated with multiple processes including epithelia mesenchymal transition, invasion and metastization. Little is known about molecular modifications of NLRP3 up-regulation. In this study, in a cohort of BCs, the expression levels of NLRP3 and PYCARD were analyzed in combination with CyclinD1 and MYC ones and their gene alterations. We described a correlation between the NLRP3/PYCARD axis and CyclinD1 (p < 0.0001). NLRP3, PYCARD and CyclinD1's positive expression was observed in estrogen receptor (ER) and progesterone receptor (PgR) positive cases (p < 0.0001). Furthermore, a reduction of NLRP3 and PYCARD expression has been observed in triple negative breast cancers (TNBCs) with respect to the Luminal phenotypes (p = 0.017 and p = 0.0015, respectively). The association NLRP3+/CCND1+ or PYCARD+/CCND1+ was related to more aggressive clinicopathological characteristics and a worse clinical outcome, both for progression free survival (PFS) and overall survival (OS) with respect to NLRP3+/CCND1− or PYCARD+/CCND1− patients, both in the whole cohort and also in the subset of Luminal tumors. In conclusion, our study shows that the NLRP3 inflammasome complex is down-regulated in TNBC compared to the Luminal subgroup. Moreover, the expression levels of NLRP3 and PYCARD together with the alterations of CCND1 results in Luminal subtype BC'ss poor prognosis.

The importance of immune checkpoints in immune monitoring: A future paradigm shift in the treatment of cancer.

The growth and development of cancer are directly correlated to the suppression of the immune system. A major breakthrough in cancer immunotherapy depends on various mechanisms to detect immunosuppressive factors that inhibit anti-tumor immune responses. Immune checkpoints are expressed on many immune cells such as T-cells, regulatory B cells (Bregs), dendritic cells (DCs), natural killer cells (NKs), regulatory T (Tregs), M2-type macrophages, and myeloid-derived suppressor cells (MDSCs). Immune inhibitory molecules, including CTLA-4, TIM-3, TIGIT, PD-1, and LAG-3, normally inhibit immune responses via negatively regulating immune cell signaling pathways to prevent immune injury. However, the up-regulation of inhibitory immune checkpoints during tumor progression on immune cells suppresses anti-tumor immune responses and promotes immune escape in cancer. It has recently been indicated that cancer cells can up-regulate various pathways of the immune checkpoints. Therefore, targeting immune inhibitory molecules through antibodies or miRNAs is a promising therapeutic strategy and shows favorable results. Immune checkpoint inhibitors (ICIs) are introduced as a new immunotherapy strategy that enhance immune cell-induced antitumor responses in many patients. In this review, we highlighted the function of each immune checkpoint on different immune cells and therapeutic strategies aimed at using monoclonal antibodies and miRNAs against inhibitory receptors. We also discussed current challenges and future strategies for maximizing these FDA-approved immunosuppressants' effectiveness and clinical success in cancer treatment.

Prognostic Value of NLRP3 Inflammasome and TLR4 Expression in Breast Cancer Patients.

Inflammasome complexes play a pivotal role in different cancer types. NOD-like receptor protein 3 (NLRP3) inflammasome is one of the most well-studied inflammasomes. Activation of the NLRP3 inflammasome induces abnormal secretion of soluble cytokines, generating advantageous inflammatory surroundings that support tumor growth. The expression levels of the NLRP3, PYCARD and TLR4 were determined by immunohistochemistry in a cohort of primary invasive breast carcinomas (BCs). We observed different NLRP3 and PYCARD expressions in non-tumor vs tumor areas (p<0.0001). All the proteins were associated to more aggressive clinicopathological characteristics (tumor size, grade, tumor proliferative activity etc.). Univariate analyses were carried out and related Kaplan-Meier curves plotted for NLRP3, PYCARD and TLR4 expression. Patients with higher NLRP3 and TLR4 expression had worse 5-year disease-free survival (DFS) compared to patients with lower NLRP3 and TLR4 expression (p =0.021 and p = 0.009, respectively). In multivariate analysis, TLR4 was confirmed as independent prognostic factors for DFS (HR = 2.03, 95% CI 1.16-3.57, p = 0.014), and high NLRP3 expression showed a slight association with DFS (HR = 1.75, 95% CI 0.98-3.15, p = 0.06). In conclusion, we showed TLR4 expression as independent prognostic factors and we highlighted for the first time that high expression of NLRP3 is linked to a poor prognosis in BC patients. These results suggest that NLRP3 and TLR4 could be two new good prognostic factor for BC patients.

PD-L1 and Notch as novel biomarkers in pancreatic sarcomatoid carcinoma: a pilot study.

BACKGROUND: The improved immunological understanding revealed the tumor microenvironment as an appealing driver to restore the immune response against cancer cells resulting in a paradigm shift in the oncology field. However, the complexity of the tumor milieu suggests the role of several pathways linking in immunomodulation mechanisms. Pancreatic cancer represents a model of the intricate relationship between malignant cells and their surrounding neighborhood. RESEARCH DESIGN AND METHODS: In this study, we analyzed, retrospectively, six cases of rare pancreatic sarcomatoid carcinoma (PSC) and evaluated the expression of PD-L1 and Notch, aiming to explore new attributes in immunophenotype. RESULTS: PD-L1 CPS ≥ 1was common in PSCs (83%) with half samples expressing PD-L1 CPS ≥ 50. Notch1 and Notch3 demonstrated a high range of expression. A direct significant correlation between PD-L1 and Notch3 overexpression (r = 0.7; p = 0.036) has been observed. Immunofluorescence studies revealed a co-localization of Notch3 and PD-L1 when both proteins were over-expressed within cytoplasmic or membranous compartments of the same cells. CONCLUSIONS: Our data identify a unique biological characterization of this rare pancreatic histotype. These findings provide a rationale for future studies evaluating the potential crosstalk between PD-L1/PD-1 axis and Notch pathways and prompting the development of novel therapeutics strategy.

NLRP3 Inflammasome From Bench to Bedside: New Perspectives for Triple Negative Breast Cancer.

The tumor microenvironment (TME) is crucial in cancer onset, progression and response to treatment. It is characterized by an intricate interaction of immune cells and cytokines involved in tumor development. Among these, inflammasomes are oligomeric molecular platforms and play a key role in inflammatory response and immunity. Inflammasome activation is initiated upon triggering of pattern recognition receptors (Toll-like receptors, NOD-like receptors, and Absent in melanoma like receptors), on the surface of immune cells with the recruitment of caspase-1 by an adaptor apoptosis-associated speck-like protein. This structure leads to the activation of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-18 and participates in different biological processes exerting its effects. To date, the Nod-Like Receptor Protein 3 (NLRP3) inflammasome has been well studied and its involvement has been established in different cancer diseases. In this review, we discuss the structure, biology and mechanisms of inflammasomes with a special focus on the specific role of NLRP3 in breast cancer (BC) and in the sub-group of triple negative BC. The NLRP3 inflammasome and its down-stream pathways could be considered novel potential tumor biomarkers and could open new frontiers in BC treatment.

Somatostatin Receptors in Merkel-Cell Carcinoma: A Therapeutic Opportunity Using Somatostatin Analog Alone or in Association With Checkpoint Inhibitors Immunotherapy. A Case Report.

Background: Merkel-cell carcinoma (MCC) is a rare, highly aggressive skin cancer typically involving elderly people. Surgery is usually the first treatment for primary tumor. In adjuvant setting, radiotherapy is effective in reducing local recurrence and in improving overall survival. Regarding advanced disease, systemic chemotherapy ended up disappointing results whereas antiPD1/antiPD-L1 immunotherapy recently gave relevant clinical benefits. Interestingly, about the half of MCC patients expresses high somatostatin receptors (SRs) to possibly represent a target for the therapeutic use of somatostatin analogs (SSAs). Nevertheless, SSAs have been little studied in MCC and cases treated with SSAs in association with checkpoint inhibitor immunotherapy have not been published yet. Case Report: We report the case of a 73-year-old man affected by metastatic MCC of right arm previously treated with surgery and adjuvant radio and chemotherapy. Three years later the patient presented loco-regional relapse involving lateral-cervical, mediastinal, and submandibular lymph nodes with high value of chromogranin A and neuron specific enolase. Due to the high expression of SRs at octreoscan and immunoistochemistry, patient started octreotide 30 mg i.m. every 28 days with a good control of disease for about 2 years. A widespread progression of disease was reported afterwards. The patient started the antiPD-L1 avelumab immunotherapy, only recently available in Italy, while still taking SSA. The patient showed an impressive regression of the disease after only four cycles of avelumab until complete remission. Conclusions: SSA could be a valid therapeutic option in patients with MCC with high SR expression. When combined with PD-1/PD-L1 immune-checkpoint inhibition, SSA is likely to enhance antiproliferative activity. Our case report provides the rationale to conduct a prospective trial and translational research to verify the efficacy and safety of combined SSA and checkpoint inhibitors for advanced MCC.