Axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC.

OBJECTIVE: The dysregulation of the axon guidance pathway is common in pancreatic ductal adenocarcinoma (PDAC), yet our understanding of its biological relevance is limited. Here, we investigated the functional role of the axon guidance cue SEMA3A in supporting PDAC progression. DESIGN: We integrated bulk and single-cell transcriptomic datasets of human PDAC with in situ hybridisation analyses of patients' tissues to evaluate SEMA3A expression in molecular subtypes of PDAC. Gain and loss of function experiments in PDAC cell lines and organoids were performed to dissect how SEMA3A contributes to define a biologically aggressive phenotype. RESULTS: In PDAC tissues, SEMA3A is expressed by stromal elements and selectively enriched in basal-like/squamous epithelial cells. Accordingly, expression of SEMA3A in PDAC cells is induced by both cell-intrinsic and cell-extrinsic determinants of the basal-like phenotype. In vitro, SEMA3A promotes cell migration as well as anoikis resistance. At the molecular level, these phenotypes are associated with increased focal adhesion kinase signalling through canonical SEMA3A-NRP1 axis. SEMA3A provides mouse PDAC cells with greater metastatic competence and favours intratumoural infiltration of tumour-associated macrophages and reduced density of T cells. Mechanistically, SEMA3A functions as chemoattractant for macrophages and skews their polarisation towards an M2-like phenotype. In SEMA3Ahigh tumours, depletion of macrophages results in greater intratumour infiltration by CD8+T cells and better control of the disease from antitumour treatment. CONCLUSIONS: Here, we show that SEMA3A is a stress-sensitive locus that promotes the malignant phenotype of basal-like PDAC through both cell-intrinsic and cell-extrinsic mechanisms.

CXCR1/2 dual-inhibitor ladarixin reduces tumour burden and promotes immunotherapy response in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with few therapeutic options available. Despite immunotherapy has revolutionised cancer treatment, the results obtained in PDAC are still disappointing. Emerging evidence suggests that chemokines/CXCRs-axis plays a pivotal role in immune tumour microenvironment modulation, which may influence immunotherapy responsiveness. Here, we evaluated the effectiveness of CXCR1/2 inhibitor ladarixin, alone or in combination with anti-PD-1, against immunosuppression in PDAC. METHODS: A set of preclinical models was obtained by engrafting mouse PDAC-derived cells into syngeneic immune-competent mice, as well as by orthotopically transplanting patient-derived PDAC tumour into human immune-system-reconstituted (HIR) mice (HuCD34-NSG-mice). Tumour-bearing mice were randomly assigned to receive vehicles, ladarixin, anti-PD-1 or drugs combination. RESULTS: CXCR1/2 inhibition by ladarixin reverted in vitro tumour-mediated M2 macrophages polarisation and migration. Ladarixin as single agent reduced tumour burden in cancer-derived graft (CDG) models with high-immunogenic potential and increased the efficacy of ICI in non-immunogenic CDG-resistant models. In a HIR mouse model bearing the immunogenic subtype of human PDAC, ladarixin showed high efficacy increasing the antitumor effect of anti-PD-1. CONCLUSION: Ladarixin in combination with anti-PD-1 might represent an extremely effective approach for the treatment of immunotherapy refractory PDAC, allowing pro-tumoral to immune-permissive microenvironment conversion.

Leptin-mediated meta-inflammation may provide survival benefit in patients receiving maintenance immunotherapy for extensive-stage small cell lung cancer (ES-SCLC).

BACKGROUND: Only few ES-SCLC patients experience long-term survival benefit by maintenance IT. Adipokines-induced metabolic meta-inflammation has been related to enhanced responsiveness to IT in obese patients; however, their prognostic role in SCLC is currently controversial. METHODS: Pre-treatment CT scan was used for determining distribution of abdominal adiposity, and blood samples were collected at fasting for measuring glycemia, insulin, ghrelin, leptin and adipokines (TNF-α, IFN-γ, IL-6 and MCP-1). Patients with known history of DM type II or metabolic syndrome with HOMA index > 2.5 were considered insulin resistant (IR). RESULTS: In ES-SCLC pts receiving maintenance IT, increased leptin concentration and higher leptin/visceral adipose tissue (VAT) ratio were significantly associated with prolonged PFS. By applying a hierarchical clustering algorithm, we identified a cluster of patients characterized by higher leptin values and lower pro-inflammatory cytokines (TNF-α, IFN-γ and IL-6) who experienced longer PFS (13.2 vs 8.05 months; HR: 0.42 [0.18-0.93] p = 0.02) and OS (18.04 vs 12.09 mo; HR: 0.53 [0.25-1.29] p = 0.07). CONCLUSIONS: Adipokines can play a crucial role to determining effectiveness of anti-cancer immunotherapy. The role of metabolic immune dysfunctions needs further pre-clinical validation and is currently investigated in the larger prospective cohort.

Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. This is due to its aggressive course, late diagnosis and its intrinsic drugs resistance. The complexity of the tumor, in terms of cell components and heterogeneity, has led to the approval of few therapies with limited efficacy. The study of the early stages of carcinogenesis provides the opportunity for the identification of actionable pathways that underpin therapeutic resistance. METHODS: We analyzed 43 Intraductal papillary mucinous neoplasms (IPMN) (12 Low-grade and 31 High-grade) by Spatial Transcriptomics. Mouse and human pancreatic cancer organoids and T cells interaction platforms were established to test the role of mucins expression on T cells activity. Syngeneic mouse model of PDAC was used to explore the impact of mucins downregulation on standard therapy efficacy. RESULTS: Spatial transcriptomics showed that mucin O-glycosylation pathway is increased in the progression from low-grade to high-grade IPMN. We identified GCNT3, a master regulator of mucins expression, as an actionable target of this pathway by talniflumate. We showed that talniflumate impaired mucins expression increasing T cell activation and recognition using both mouse and human organoid interaction platforms. In vivo experiments showed that talniflumate was able to increase the efficacy of the chemotherapy by boosting immune infiltration. CONCLUSIONS: Finally, we demonstrated that combination of talniflumate, an anti-inflammatory drug, with chemotherapy effectively improves anti-tumor effect in PDAC.

KRAS-Dependency in Pancreatic Ductal Adenocarcinoma: Mechanisms of Escaping in Resistance to KRAS Inhibitors and Perspectives of Therapy.

Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers in oncology because of its increasing incidence and poor survival rate. More than 90% of PDAC patients are KRAS mutated (KRASmu), with KRASG12D and KRASG12V being the most common mutations. Despite this critical role, its characteristics have made direct targeting of the RAS protein extremely difficult. KRAS regulates development, cell growth, epigenetically dysregulated differentiation, and survival in PDAC through activation of key downstream pathways, such as MAPK-ERK and PI3K-AKT-mammalian target of rapamycin (mTOR) signaling, in a KRAS-dependent manner. KRASmu induces the occurrence of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) and leads to an immunosuppressive tumor microenvironment (TME). In this context, the oncogenic mutation of KRAS induces an epigenetic program that leads to the initiation of PDAC. Several studies have identified multiple direct and indirect inhibitors of KRAS signaling. Therefore, KRAS dependency is so essential in KRASmu PDAC that cancer cells have secured several compensatory escape mechanisms to counteract the efficacy of KRAS inhibitors, such as activation of MEK/ERK signaling or YAP1 upregulation. This review will provide insights into KRAS dependency in PDAC and analyze recent data on inhibitors of KRAS signaling, focusing on how cancer cells establish compensatory escape mechanisms.

Intraductal Pancreatic Mucinous Neoplasms: A Tumor-Biology Based Approach for Risk Stratification.

Pancreatic ductal adenocarcinoma is one of the most lethal human cancers. Its precursor lesions include pancreatic intra-epithelial neoplasia, mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm (IPMN). IPMNs usually present as an incidental finding at imaging in 2.6% of the population and, according to the degree of dysplasia, they are classified as low- or high-grade lesions. Since the risk of malignant transformation is not accurately predictable, the management of these lesions is based on morphological and clinical parameters, such as presence of mural nodule, main pancreatic duct dilation, presence of symptoms, or high-grade dysplasia. Although the main genetic alterations associated to IPMNs have been elucidated, they are still not helpful for disease risk stratification. The growing body of genomic and epigenomic studies along with the more recent development of organotypic cultures provide the opportunity to improve our understanding of the malignant transformation process, which will likely deliver biomarkers to help discriminate between low- and high-risk lesions. Recent insights on the topic are herein summarized.

Lung and Gut Microbiota as Potential Hidden Driver of Immunotherapy Efficacy in Lung Cancer.

Lung cancer is one of the deadliest and most common malignancies in the world, representing one of the greatest challenges in cancer treatment. Immunotherapy is rapidly changing standard treatment schedule and outcomes for patients with advanced malignancies. However, several ongoing studies are still attempting to elucidate the biomarkers that could predict treatment response as well as the new strategies to improve antitumor immune system response ameliorating immunotherapy efficacy. The complex of bacteria, fungi, and other microorganisms, termed microbiota, that live on the epithelial barriers of the host, are involved in the initiation, progression, and dissemination of cancer. The functional role of microbiota has attracted an accumulating attention recently. Indeed, it has been demonstrated that commensal microorganisms are required for the maturation, education, and function of the immune system regulating the efficacy of immunotherapy in the anticancer response. In this review, we discuss some of the major findings depicting bacteria as crucial gatekeeper for the immune response against tumor and their role as driver of immunotherapy efficacy in lung cancer with a special focus on the distinctive role of gut and lung microbiota in the efficacy of immunotherapy treatment.

TAK-ing aim at chemoresistance: The emerging role of MAP3K7 as a target for cancer therapy.

Cellular drug resistance remains the main obstacle to the clinical efficacy of cancer chemotherapy. Alterations in key pathways regulating cell cycle checkpoints, apoptosis and Epithelial to Mesenchymal Transition (EMT), such as the Mitogen-activated protein kinase (MAPK) pathway, appear to be closely associated to cancer chemoresistance. Transforming growth factor-ß (TGF-ß)- activated kinase 1 (TAK1, also known as MAP3K7) is a serine/threonine kinase in the mitogen-activated protein kinase (MAP3K) family. It represents the cellular hub to which IL1, TGF-ß and Wnt signaling pathways converge. By regulating the phosphorylation status and activities of transcription factors including Activated Protein-1 (AP-1) and nuclear factor κ-B (NF-κB), TAK1 mediates inflammatory and pro-survival responses. The interest towards the therapeutic targeting of TAK1 is due to its identification as one of the main mediators of both chemoresistance and EMT in several types of tumors, and as the possible target for a subset of treatment-refractory colon cancers exhibiting mutated KRAS or activated WNT pathways. For these reasons, many efforts have been made to design inhibitors of TAK1 kinase activity, which could be used to reverse TAK1-mediated chemoresistance. The activity of these inhibitors, in combination with the most commonly used chemotherapeutic drugs, has been tested in preclinical studies, proving the efficacy of TAK1 inhibition in reducing tumor growth and survival following chemotherapy administration. In the first part of this review, we describe the mechanisms underlying TAK1 regulation such as phosphorylation, ubiquitination and targeting by microRNAs. We then focus on the development of therapeutic small molecule inhibitors of TAK1 kinase activity, as well as preclinical studies supporting the role of TAK1 as a potential target for enhancing the response of tumors to anticancer therapies.

Pancreatic Cancer and Obesity: Molecular Mechanisms of Cell Transformation and Chemoresistance.

Cancer and obesity are the two major epidemics of the 21st century. Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of death, with a five-year overall survival rate of only 8%. Its incidence and mortality have increased in recent years, and this cancer type is expected to be among the top five leading causes of cancer-related death by 2030 in the United States (US). In the last three decades, the prevalence of overweight people has boosted with a consequent increase in obesity-related diseases. Considerable epidemiologic evidence correlates overweight and obese conditions to an increased risk of several types of cancer, including PDAC. Besides being a risk factor for multiple metabolic disorders, the tumor-promoting effects of obesity occur at the local level via inflammatory mediators that are associated with adipose inflammation and metabolic or hormones mediators and microbiota dysbiosis. Although an excess of body mass index (BMI) represents the second most modifiable risk factor for PDAC with an increased cancer related-death of more than 20⁻40%, still little is known about the molecular mechanisms that underlie this strong association. In this review, we focused on the role of obesity as a preventable risk factor of PDAC, discussing the molecular mechanisms linking obesity to cancer initiation and progression. Moreover, we highlighted the role of obesity in defining chemoresistance, showing how a high BMI can actually reduce response to chemotherapy.

Angiopoietin-Like Proteins in Angiogenesis, Inflammation and Cancer.

Altered expression of secreted factors by tumor cells or cells of the tumor microenvironment is a key event in cancer development and progression. In the last decade, emerging evidences supported the autocrine and paracrine activity of the members of the Angiopoietin-like (ANGPTL) protein family in angiogenesis, inflammation and in the regulation of different steps of carcinogenesis and metastasis development. Thus, ANGPTL proteins become attractive either as prognostic or predictive biomarkers, or as novel target for cancer treatment. Here, we outline the current knowledge about the functions of the ANGPTL proteins in angiogenesis, cancer progression and metastasis. Moreover, we discuss the most recent evidences sustaining their role as prognostic or predictive biomarkers for cancer therapy. Although the role of ANGPTL proteins in cancer has not been fully elucidated, increasing evidence suggest their key effects in the proliferative and invasive properties of cancer cells. Moreover, given the common overexpression of ANGPTL proteins in several aggressive solid tumors, and their role in tumor cells and cells of the tumor microenvironment, the field of research about ANGPTL proteins network may highlight new potential targets for the development of future therapeutic strategies.

Tissue transglutaminase (TG2) is involved in the resistance of cancer cells to the histone deacetylase (HDAC) inhibitor vorinostat.

Vorinostat demonstrated preclinical and clinical efficacy in human cancers and is the first histone deacetylase inhibitor (HDACi) approved for cancer treatment. Tissue transglutaminase (TG2) is a multifunctional enzyme that catalyzes a Ca2+ dependent transamidating reaction resulting in covalent cross-links between proteins. TG2 acts also as G-protein in trans-membrane signaling and as a cell surface adhesion mediator. TG2 up-regulation has been demonstrated in several cancers and its expression levels correlate with resistance to chemotherapy and metastatic potential. We demonstrated that the anti-proliferative effect of the HDACi vorinostat is paralleled by the induction of TG2 mRNA and protein expression in cancer cells but not in ex vivo treated peripheral blood lymphocytes. This effect was also shared by other pan-HDACi and resulted in increased TG2 transamidating activity. Notably, high TG2 basal levels in a panel of cancer cell lines correlated with lower vorinostat antiproliferative activity. Notably, in TG2-knockdown cancer cells vorinostat anti-proliferative and pro-apoptotic effects were enhanced, whereas in TG2-full-length transfected cells were impaired, suggesting that TG2 could represent a mechanism of intrinsic or acquired resistance to vorinostat. In fact, co-treatment of tumor cells with inhibitors of TG2 transamidating activity potentiated the antitumor effect of vorinostat. Moreover, vorinostat-resistant MCF7 cells selected by stepwise increasing concentrations of the drug, significantly overexpressed TG2 protein compared to parental cells, and co-treatment of these cells with TG2 inhibitors reversed vorinostat-resistance. Taken together, our data demonstrated that TG2 is involved in the resistance of cancer cells to vorinostat, as well as to other HDACi.

Combined inhibition of IL1, CXCR1/2, and TGFß signaling pathways modulates in-vivo resistance to anti-VEGF treatment.

Resistance of tumors to antiangiogenic therapies is becoming increasingly relevant. We recently identified interleukin-1 (IL1), CXC receptors (CXCR)1/2 ligands, and transforming growth factor ß (TGFß) among the proinflammatory factors that were expressed at higher levels in murine models resistant to the antivascular endothelial growth factor (anti-VEGF) antibody bevacizumab. Here, we hypothesized that the combined inhibition of these proinflammatory signaling pathways might reverse this anti-VEGF resistance. Bevacizumab-resistant FGBR pancreatic cancer cells were treated in vitro with bevacizumab, the recombinant human IL1 receptor antagonist anakinra, the monoclonal antibody against TGFß receptor type II TR1, and a novel recombinant antibody binding CXCR1/2 ligands. The FGBR cells treated with these agents in combination had significantly higher levels of E-cadherin and lower levels of vimentin, IL6, phosphorylated p65, and SMAD2, and showed significantly lower migration rates than did their controls treated with the same agents without bevacizumab or with a single agent bevacizumab as a control. Consistently, the combination of these agents with bevacizumab reduced the FGBR tumor burden and significantly prolonged mice survival compared with bevacizumab in monotherapy. Tumors from mice receiving the combination treatment showed significantly lower expression of IL6 and phosphorylated SMAD2, higher expression of E-cadherin and lower levels of vimentin, and a significantly lower infiltration by CD11b cells compared with bevacizumab-treated controls. This study suggests that inhibition of IL1, CXCR1/2, and TGFß signaling pathways is a potential therapeutic approach to modulate the acquired resistance to anti-VEGF treatment by reversing epithelial-mesenchymal transition and inhibiting CD11b proangiogenic myeloid cells' tumor infiltration.

Prognostic role of circulating cytokines and inflammation indexes for avelumab maintenance in metastatic urothelial carcinoma.

Background: Avelumab maintenance after first-line platinum-based chemotherapy represents a cornerstone for the treatment of metastatic urothelial carcinoma (mUC). However, identifying prognostic biomarkers is paramount for optimizing patients' benefits while minimizing toxicity. Cytokines represent circulating mediators of the complex interaction between cancer, the immune system, and inflammation. Inflammation, a hallmark of cancer, can be expressed by circulating factors. In different tumor subtypes, peripheral blood biomarkers, such as circulating cytokines, and systemic inflammatory indexes, have been addressed as potential prognostic factors for immune checkpoint inhibitors. However, their role in mUC still needs to be determined. Methods: Between February 2021 and April 2023, we prospectively collected plasma cytokines and inflammation indexes in 28 patients with mUC before starting avelumab as first-line maintenance. The primary endpoint was the relationship between baseline cytokines and inflammatory indexes with the clinical benefit (CB), defined as the number of Responders. Secondary endpoints included the correlation of baseline cytokines and inflammatory indexes with progression-free survival (PFS), overall survival (OS), and the number and grade of immune-related adverse events. Results: High pre-treatment levels of interferon (IFN)-γ and interleukin (IL)-2, and low levels of IL-6, IL-8, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and systemic-inflammation index (SII) were associated with clinical benefit and longer survival. In the multivariate analysis, low IL-8, NLR, and SII levels maintained a positive prognostic value for OS. Conclusion: Our data suggest that, in mUC patients receiving avelumab, pre-treatment levels of plasma cytokines and inflammatory indexes may serve as potential prognostic biomarkers for response and efficacy. In particular, patients with signs of pre-therapeutic inflammation showed a significantly lower response and survival to avelumab. On the contrary, low systemic inflammation and high levels of cytokines characterized responders and longer survivors.

The Role of the Complement in Clear Cell Renal Carcinoma (ccRCC)-What Future Prospects Are There for Its Use in Clinical Practice?

In recent years, the first-line available therapeutic options for metastatic renal cell carcinoma (mRCC) have radically changed with the introduction into clinical practice of new immune checkpoint inhibitor (ICI)-based combinations. Many efforts are focusing on identifying novel prognostic and predictive markers in this setting. The complement system (CS) plays a central role in promoting the growth and progression of mRCC. In particular, mRCC has been defined as an "aggressive complement tumor", which encompasses a group of malignancies with poor prognosie and highly expressed complement components. Several preclinical and retrospective studies have demonstrated the negative prognostic role of the complement in mRCC; however, there is little evidence on its possible role as a predictor of the response to ICIs. The purpose of this review is to explore more deeply the physio-pathological role of the complement in the development of RCC and its possible future use in clinical practice as a prognostic and predictive factor.

Identification of spatially-resolved markers of malignant transformation in Intraductal Papillary Mucinous Neoplasms.

The existing Intraductal Papillary Mucinous Neoplasm (IPMN) risk stratification relies on clinical and histological factors, resulting in inaccuracies and leading to suboptimal treatment. This is due to the lack of appropriate molecular markers that can guide patients toward the best therapeutic options. Here, we assess and confirm subtype-specific markers for IPMN across two independent cohorts of patients using two Spatial Transcriptomics (ST) technologies. Specifically, we identify HOXB3 and ZNF117 as markers for Low-Grade Dysplasia, SPDEF and gastric neck cell markers in borderline cases, and NKX6-2 and gastric isthmus cell markers in High-Grade-Dysplasia Gastric IPMN, highlighting the role of TNFα and MYC activation in IPMN progression and the role of NKX6-2 in the specific Gastric IPMN progression. In conclusion, our work provides a step forward in understanding the gene expression landscapes of IPMN and the critical transcriptional networks related to PDAC progression.

CSF CXCL13 and Chitinase 3-like-1 Levels Predict Disease Course in Relapsing Multiple Sclerosis.

Several biomarkers from multiple sclerosis (MS) patients' biological fluids have been considered to support diagnosis, predict disease course, and evaluate treatment response. In this study, we assessed the CSF concentration of selected molecules implicated in the MS pathological process. To investigate the diagnostic and prognostic significance of CSF concentration of target candidate biomarkers in both relapsing (RMS, n = 107) and progressive (PMS, n = 18) MS patients and in other inflammatory (OIND, n = 10) and non-inflammatory (ONIND, n = 15) neurological disorders. We measured the CSF concentration of APRIL, BAFF, CHI3L1, CCL-2, CXCL-8, CXCL-10, CXCL-12, CXCL-13 through a Luminex Assay. MS patients were prospectively evaluated, and clinical and radiological activity were recorded. CHI3L1 and CXCL13 CSF levels were significantly higher in both MS groups compared to control groups, while CCL2, BAFF, and APRIL concentrations were lower in RMS patients compared to PMS and OIND. Considering RMS patients with a single demyelinating event, higher concentrations of CHI3L1, CXCL10, CXCL12, and CXCL13 were recorded in patients who converted to clinically defined MS(CDMS). RMS patients in the CXCL13 and CHI3L1 high concentration group had a significantly higher risk of relapse (HR 12.61 and 4.57), MRI activity (HR 7.04 and 2.46), and of any evidence of disease activity (HR 12.13 and 2.90) during follow-up. CSF CXCL13 and CHI3L1 levels represent very good prognostic biomarkers in RMS patients, and therefore can be helpful in the treatment choice. Higher CSF concentrations of neuro-inflammatory biomarkers were associated with a higher risk of conversion to CDMS in patients with a first clinical demyelinating event. Differential CSF BAFF and APRIL levels between RMS and PMS suggest a different modulation of B-cells pathways in the different phases of the disease.

Immune checkpoint blockade therapy mitigates systemic inflammation and affects cellular FLIP-expressing monocytic myeloid-derived suppressor cells in non-progressor non-small cell lung cancer patients.

Cancer cells favor the generation of myeloid cells with immunosuppressive and inflammatory features, including myeloid-derived suppressor cells (MDSCs), which support tumor progression. The anti-apoptotic molecule, cellular FLICE (FADD-like interleukin-1ß-converting enzyme)-inhibitory protein (c-FLIP), which acts as an important modulator of caspase-8, is required for the development and function of monocytic (M)-MDSCs. Here, we assessed the effect of immune checkpoint inhibitor (ICI) therapy on systemic immunological landscape, including FLIP-expressing MDSCs, in non-small cell lung cancer (NSCLC) patients. Longitudinal changes in peripheral immunological parameters were correlated with patients' outcome. In detail, 34 NSCLC patients were enrolled and classified as progressors (P) or non-progressors (NP), according to the RECIST evaluation. We demonstrated a reduction in pro-inflammatory cytokines such as IL-8, IL-6, and IL-1ß in only NP patients after ICI treatment. Moreover, using t-distributed stochastic neighbor embedding (t-SNE) and cluster analysis, we characterized in NP patients a significant increase in the amount of lymphocytes and a slight contraction of myeloid cells such as neutrophils and monocytes. Despite this moderate ICI-associated alteration in myeloid cells, we identified a distinctive reduction of c-FLIP expression in M-MDSCs from NP patients concurrently with the first clinical evaluation (T1), even though NP and P patients showed the same level of expression at baseline (T0). In agreement with the c-FLIP expression, monocytes isolated from both P and NP patients displayed similar immunosuppressive functions at T0; however, this pro-tumor activity was negatively influenced at T1 in the NP patient cohort exclusively. Hence, ICI therapy can mitigate systemic inflammation and impair MDSC-dependent immunosuppression.

Gastrointestinal Cancer Patient Nutritional Management: From Specific Needs to Novel Epigenetic Dietary Approaches.

Nutritional habits impinge on the health of the gastrointestinal (GI) tract, contributing to GI disorder progression. GI cancer is a widespread and aggressive tumor sensitive to nutritional changes. Indeed, specific nutritional expedients can be adopted to prevent GI cancer onset and to slow down disease activity. Moreover, the patient's nutritional status impacts prognosis, quality of life, and chemotherapy tolerance. These patients encounter the highest frequency of malnourishment risk, a condition that can progressively evolve into cachexia. Clinical studies dealing with this topic stressed the importance of nutritional counseling and put under the spotlight nutrient delivery, the type of nutrient supplementation, and timing for the start of nutritional management. A medical practitioner well-prepared on the topic of nutrition and cancer should operate in the clinical team dedicated to these oncological patients. This specific expertise needs to be implemented as soon as possible to adopt nutritional interventions and establish a proper patient-tailored dietary regimen. The nutritional gap closure should be prompt during anticancer treatment to stabilize weight loss, improve treatment tolerability, and ameliorate survival rate. Recently, novel nutritional approaches were investigated to target the bidirectional link between epigenetics and metabolism, whose alteration supports the onset, progression, and therapeutic response of GI cancer patients.

Immunogenic Cell Death: An Emerging Target in Gastrointestinal Cancers.

Immunogenic cell death (ICD) is a regulated form of cell death that induces the activation of both innate and adaptive immune responses through the release of damage-associated molecular patterns (DAMPs) and their subsequent recognition by pattern-recognition receptors (PRRs), generating specific CD8+ T lymphocytes. Thus, ICD inducers (such as certain chemotherapeutic agents, targeted therapies, radiation, and oncolytic viruses) could become a potential cancer treatment by providing antitumour immunity and cancer vaccination. Moreover, their combination with immunotherapy, especially with immune checkpoint inhibitors, could overcome the immunosuppressive tumour microenvironment that characterises certain cancers, including gastrointestinal cancers. This review will provide insights into the role of ICD induction in colorectal, gastric, pancreatic, and hepatocellular carcinomas. Specifically, we will discuss the main mechanisms involved in ICD, their potential application in gastrointestinal cancer treatment, and the latest clinical trial updates.