Classification of tumor types using XGBoost machine learning model: a vector space transformation of genomic alterations.

BACKGROUND: Machine learning (ML) represents a powerful tool to capture relationships between molecular alterations and cancer types and to extract biological information. Here, we developed a plain ML model aimed at distinguishing cancer types based on genetic lesions, providing an additional tool to improve cancer diagnosis, particularly for tumors of unknown origin. METHODS: TCGA data from 9,927 samples spanning 32 different cancer types were downloaded from cBioportal. A vector space model type data transformation technique was designed to build consistently homogeneous new datasets containing, as predictive features, calls for somatic point mutations and copy number variations at chromosome arm-level, thus allowing the use of the XGBoost classifier models. Considering the imbalance in the dataset, due to large difference in the number of cases for each tumor, two preprocessing strategies were considered: i) setting a percentage cut-off threshold to remove less represented cancer types, ii) dividing cancer types into different groups based on biological criteria and training a specific XGBoost model for each of them. The performance of all trained models was mainly assessed by the out-of-sample balanced accuracy (BACC) and the AUC scores. RESULTS: The XGBoost classifier achieved the best performance (BACC 77%; AUC 97%) on a dataset containing the 10 most represented tumor types. Moreover, dividing the 18 most represented cancers into three different groups (endocrine-related carcinomas, other carcinomas and other cancers),such analysis models achieved 78%, 71% and 86% BACC, respectively, with AUC scores greater than 96%. In addition, the model capable of linking each group to a specific cancer type reached 81% BACC and 94% AUC. Overall, the diagnostic potential of our model was comparable/higher with respect to others already described in literature and based on similar molecular data and ML approaches. CONCLUSIONS: A boosted ML approach able to accurately discriminate different cancer types was developed. The methodology builds datasets simpler and more interpretable than the original data, while keeping enough information to accurately train standard ML models without resorting to sophisticated Deep Learning architectures. In combination with histopathological examinations, this approach could improve cancer diagnosis by using specific DNA alterations, processed by a replicable and easy-to-use automated technology. The study encourages new investigations which could further increase the classifier's performance, for example by considering more features and dividing tumors into their main molecular subtypes.

MiR-182-5p Is Upregulated in Hepatic Tissues from a Diet-Induced NAFLD/NASH/HCC C57BL/6J Mouse Model and Modulates Cyld and Foxo1 Expression.

Non-alcoholic fatty liver disease (NAFLD) is considered a relevant liver chronic disease. Variable percentages of NAFLD cases progress from steatosis to steatohepatitis (NASH), cirrhosis and, eventually, hepatocellular carcinoma (HCC). In this study, we aimed to deepen our understanding of expression levels and functional relationships between miR-182-5p and Cyld-Foxo1 in hepatic tissues from C57BL/6J mouse models of diet-induced NAFL/NASH/HCC progression. A miR-182-5p increase was detected early in livers as NAFLD damage progressed, and in tumors compared to peritumor normal tissues. An in vitro assay on HepG2 cells confirmed Cyld and Foxo1, both tumor-suppressor, as miR-182-5p target genes. According to miR-182-5p expression, decreased protein levels were observed in tumors compared to peritumor tissues. Analysis of miR-182-5p, Cyld and Foxo1 expression levels, based on datasets from human HCC samples, showed results consistent with those from our mouse models, and also highlighted the ability of miR-182-5p to distinguish between normal and tumor tissues (AUC 0.83). Overall, this study shows, for the first time, miR-182-5p overexpression and Cyld-Foxo1 downregulation in hepatic tissues and tumors from a diet-induced NAFLD/HCC mouse model. These data were confirmed by the analysis of datasets from human HCC samples, highlighting miR-182-5p diagnostic accuracy and demonstrating the need for further studies to assess its potential role as a biomarker or therapeutic target.

NF-κB and mitochondria cross paths in cancer: mitochondrial metabolism and beyond.

NF-κB plays a pivotal role in oncogenesis. This transcription factor is best known for promoting cancer cell survival and tumour-driving inflammation. However, several lines of evidence support a crucial role for NF-κB in governing energy homeostasis and mediating cancer metabolic reprogramming. Mitochondria are central players in many metabolic processes altered in cancer. Beyond their bioenergetic activity, several facets of mitochondria biology, including mitochondrial dynamics and oxidative stress, promote and sustain malignant transformation. Recent reports revealed an intimate connection between NF-κB pathway and the oncogenic mitochondrial functions. NF-κB can impact mitochondrial respiration and mitochondrial dynamics, and, reciprocally, mitochondria can sense stress signals and convert them into cell biological responses leading to NF-κB activation. In this review we discuss their emerging reciprocal regulation and the significance of this interplay for anticancer therapy.

MicroRNAs Expression in Response to rhNGF in Epithelial Corneal Cells: Focus on Neurotrophin Signaling Pathway.

PURPOSE: Nerve growth factor efficacy was demonstrated for corneal lesions treatment, and recombinant human NGF (rhNGF) was approved for neurotrophic keratitis therapy. However, NGF-induced molecular responses in cornea are still largely unknown. We analyzed microRNAs expression in human epithelial corneal cells after time-dependent rhNGF treatment. METHODS: Nearly 700 microRNAs were analyzed by qRT-PCR. MicroRNAs showing significant expression differences were examined by DIANA-miRpath v.3.0 to identify target genes and pathways. Immunoblots were performed to preliminarily assess the strength of the in silico results. RESULTS: Twenty-one microRNAs (miR-26a-1-3p, miR-30d-3p, miR-27b-5p, miR-146a-5p, miR-362-5p, mir-550a-5p, mir-34a-3p, mir-1227-3p, mir-27a-5p, mir-222-5p, mir-151a-5p, miR-449a, let7c-5p, miR-337-5p, mir-29b-3p, miR-200b-3p, miR-141-3p, miR-671-3p, miR-324-5p, mir-411-3p, and mir-425-3p) were significantly regulated in response to rhNGF. In silico analysis evidenced interesting target genes and pathways, including that of neurotrophin, when analyzed in depth. Almost 80 unique target genes (e.g., PI3K, AKT, MAPK, KRAS, BRAF, RhoA, Cdc42, Rac1, Bax, Bcl2, FasL) were identified as being among those most involved in neurotrophin signaling and in controlling cell proliferation, growth, and apoptosis. AKT and RhoA immunoblots demonstrated congruence with microRNA expression, providing preliminary validation of in silico data. CONCLUSIONS: MicroRNA levels in response to rhNGF were for the first time analyzed in corneal cells. Novel insights about microRNAs, target genes, pathways modulation, and possible biological responses were provided. Importantly, given the putative role of microRNAs as biomarkers or therapeutic targets, our results make available data which might be potentially exploitable for clinical applications.

Cancer secretome and inflammation: The bright and the dark sides of NF-κB.

Tumour promoting inflammation is widely recognized as a hallmark of cancer. The source of this chronic inflammation in cancer has been ascribed to the progressive activation over time of immune cells, mostly of the innate arm of the immune system. However, recent evidence has shown that chronic inflammation may also derive, at least in part, from senescent cells. Hence, due to the prominent role of inflammation in cancer, the cancer secretome definition includes all the secretory factors ensuing from the crosstalk between the cancer cell and the tumour microenvironment. The mechanistic basis underlying the paracrine signalling between the cancer cell and the surrounding tumour microenvironment in malignancy have been widely investigated by using in vivo models of cancers, thus identifying the NF-κB transcription factor as the molecular hub linking inflammation and cancer. In this review, we highlight the roles of NF-κB in regulating the inflammation-derived secretome emanating from immune and senescent cells, with a special focus on the bright and the dark sides of their pro-inflammatory signalling on tumorigenesis.

Leptin in Tumor Microenvironment.

Leptin is a hormone that plays a major role as mediator of long-term regulation of energy balance, suppressing food intake, and stimulating weight loss. More recently, important physiological roles other than controlling appetite and energy expenditure have been suggested for leptin, including neuroendocrine, reparative, reproductive, and immune functions. These emerging peripheral roles let hypothesize that leptin can modulate also cancer progression. Indeed, many studies have demonstrated that elevated chronic serum concentrations of leptin, frequently seen in obese subjects, represent a stimulatory signal for tumor growth. Current knowledge indicates that also different non-tumoral cells resident in tumor microenvironment may respond to leptin creating a favorable soil for cancer cells. In addition, leptin is produced also within the tumor microenvironment creating the possibility for paracrine and autocrine action. In this review, we describe the main mechanisms that regulate peripheral leptin availability and how leptin can shape tumor microenvironment.

Effects of reduced natural background radiation on Drosophila melanogaster growth and development as revealed by the FLYINGLOW program.

Natural background radiation of Earth and cosmic rays played a relevant role during the evolution of living organisms. However, how chronic low doses of radiation can affect biological processes is still unclear. Previous data have indicated that cells grown at the Gran Sasso Underground Laboratory (LNGS, L'Aquila) of National Institute of Nuclear Physics (INFN) of Italy, where the dose rate of cosmic rays and neutrons is significantly reduced with respect to the external environment, elicited an impaired response against endogenous damage as compared to cells grown outside LNGS. This suggests that environmental radiation contributes to the development of defense mechanisms at cellular level. To further understand how environmental radiation affects metabolism of living organisms, we have recently launched the FLYINGLOW program that aims at exploiting Drosophila melanogaster as a model for evaluating the effects of low doses/dose rates of radiation at the organismal level. Here, we will present a comparative data set on lifespan, motility and fertility from different Drosophila strains grown in parallel at LNGS and in a reference laboratory at the University of L'Aquila. Our data suggest the reduced radiation environment can influence Drosophila development and, depending on the genetic background, may affect viability for several generations even when flies are moved back to normal background radiation. As flies are considered a valuable model for human biology, our results might shed some light on understanding the effect of low dose radiation also in humans.

Next-generation sequencing: recent applications to the analysis of colorectal cancer.

Since the establishment of the Sanger sequencing method, scientists around the world focused their efforts to progress in the field to produce the utmost technology. The introduction of next-generation sequencing (NGS) represents a revolutionary step and promises to lead to massive improvements in our understanding on the role of nucleic acids functions. Cancer research began to use this innovative and highly performing method, and interesting results started to appear in colorectal cancer (CRC) analysis. Several studies produced high-quality data in terms of mutation discovery, especially about actionable or less frequently mutated genes, epigenetics, transcriptomics. Analysis of results is unveiling relevant perspectives aiding to evaluate the response to therapies. Novel evidences have been presented also in other directions such as gut microbiota or CRC circulating tumor cells. However, despite its unquestioned potential, NGS poses some issues calling for additional studies. This review intends to offer a view of the state of the art of NGS applications to CRC through examination of the most important technologies and discussion of recent published results.

MicroRNA expression analysis in high fat diet-induced NAFLD-NASH-HCC progression: study on C57BL/6J mice.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Non-alcoholic fatty liver disease (NAFLD) is a frequent chronic liver disorder in developed countries. NAFLD can progress through the more severe non alcoholic steatohepatitis (NASH), cirrhosis and, lastly, HCC. Genetic and epigenetic alterations of coding genes as well as deregulation of microRNAs (miRNAs) activity play a role in HCC development. In this study, the C57BL/6J mouse model was long term high-fat (HF) or low-fat (LF) diet fed, in order to analyze molecular mechanisms responsible for the hepatic damage progression. METHODS: Mice were HF or LF diet fed for different time points, then plasma and hepatic tissues were collected. Histological and clinical chemistry assays were performed to assess the progression of liver disease. MicroRNAs' differential expression was evaluated on pooled RNAs from tissues, and some miRNAs showing dysregulation were further analyzed at the individual level. RESULTS: Cholesterol, low and high density lipoproteins, triglycerides and alanine aminotransferase increase was detected in HF mice. Gross anatomical examination revealed hepatomegaly in HF livers, and histological analysis highlighted different degrees and levels of steatosis, inflammatory infiltrate and fibrosis in HF and LF animals, demonstrating the progression from NAFLD through NASH. Macroscopic nodules, showing typical neoplastic features, were observed in 20% of HF diet fed mice. Fifteen miRNAs differentially expressed in HF with respect to LF hepatic tissues during the progression of liver damage, and in tumors with respect to HF non tumor liver specimens were identified. Among them, miR-340-5p, miR-484, miR-574-3p, miR-720, whose expression was never described in NAFLD, NASH and HCC tissues, and miR-125a-5p and miR-182, which showed early and significant dysregulation in the sequential hepatic damage process. CONCLUSIONS: In this study, fifteen microRNAs which were modulated in hepatic tissues and in tumors during the transition NAFLD-NASH-HCC are reported. Besides some already described, new and early dysregulated miRNAs were identified. Functional analyses are needed to validate the results here obtained, and to better define the role of these molecules in the progression of the hepatic disease.

Bioinformatics approach to predict target genes for dysregulated microRNAs in hepatocellular carcinoma: study on a chemically-induced HCC mouse model.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive epithelial tumor which shows very poor prognosis and high rate of recurrence, representing an urgent problem for public healthcare. MicroRNAs (miRNAs/miRs) are a class of small, non-coding RNAs that attract great attention because of their role in regulation of processes such as cellular growth, proliferation, apoptosis. Because of the thousands of potential interactions between a single miR and target mRNAs, bioinformatics prediction tools are very useful to facilitate the task for individuating and selecting putative target genes. In this study, we present a chemically-induced HCC mouse model to identify differential expression of miRNAs during the progression of the hepatic injury up to HCC onset. In addition, we describe an established bioinformatics approach to highlight putative target genes and protein interaction networks where they are involved. RESULTS: We describe four miRs (miR-125a-5p, miR-27a, miR-182, miR-193b) which showed to be differentially expressed in the chemically-induced HCC mouse model. The miRs were subjected to four of the most used predictions tools and 15 predicted target genes were identified. The expression of one (ANK3) among the 15 predicted targets was further validated by immunoblotting. Then, enrichment annotation analysis was performed revealing significant clusters, including some playing a role in ion transporter activity, regulation of receptor protein serine/threonine kinase signaling pathway, protein import into nucleus, regulation of intracellular protein transport, regulation of cell adhesion, growth factor binding, and regulation of TGF-beta/SMAD signaling pathway. A network construction was created and links between the selected miRs, the predicted targets as well as the possible interactions among them and other proteins were built up. CONCLUSIONS: In this study, we combined miRNA expression analysis, obtained by an in vivo HCC mouse model, with a bioinformatics-based workflow. New genes, pathways and protein interactions, putatively involved in HCC initiation and progression, were identified and explored.

The role of IL-1ß in the bone loss during rheumatic diseases.

Several inflammatory diseases have been associated with increased bone resorption and fracture rates and different studies supported the relation between inflammatory cytokines and osteoclast activity. The main factor required for osteoclast activation is the stimulation by receptor activator of nuclear factor kappa-B ligand (RANKL) expressed on osteoblasts. In this context, interleukin- (IL-) 1ß, one of the most powerful proinflammatory cytokines, is a strong stimulator of in vitro and in vivo bone resorption via upregulation of RANKL that stimulates the osteoclastogenesis. The resulting effects lead to an imbalance in bone metabolism favouring bone resorption and osteoporosis. In this paper, we review the available literature on the role of IL-1ß in the pathogenesis of bone loss. Furthermore, we analysed the role of IL-1ß in bone resorption during rheumatic diseases and, when available, we reported the efficacy of anti-IL-1ß therapy in this field.

Takotsubo Syndrome during Pertuzumab and Trastuzumab Therapy for HER2-Positive Metastatic Breast Cancer.

Pertuzumab and trastuzumab have been shown to improve the outcomes of patients with metastatic breast cancer, with a rate of left ventricular dysfunction of approximately 6%. We report the case of a postmenopausal woman who presented with Takotsubo syndrome during maintenance therapy with pertuzumab and trastuzumab, in association with fulvestrant (an anti-estrogen) and denosumab. After normalization of cardiac function, therapy with pertuzumab and trastuzumab was resumed in the absence of new cardiac toxicity. We report the first clinical case of Takotsubo syndrome during double anti-HER2 blockade in association with an antiestrogen. Furthermore, we show how anti-HER2 therapy can be safely resumed after the detection of Takotsubo syndrome.

Role of Breast Cancer Risk Estimation Models to Identify Women Eligible for Genetic Testing and Risk-Reducing Surgery.

Hereditary breast and ovarian cancer (HBOC) syndrome is responsible for approximately 10% of breast cancers (BCs). The HBOC gene panel includes both high-risk genes, i.e., a four times higher risk of BC (BRCA1, BRCA2, PALB2, CDH1, PTEN, STK11 and TP53), and moderate-risk genes, i.e., a two to four times higher risk of BC (BARD1, CHEK2, RAD51C, RAD51D and ATM). Pathogenic germline variants (PGVs) in HBOC genes confer an absolute risk of BC that changes according to the gene considered. We illustrate and compare different BC risk estimation models, also describing their limitations. These models allow us to identify women eligible for genetic testing and possibly to offer surgical strategies for primary prevention, i.e., risk-reducing mastectomies and salpingo-oophorectomies.

A method to comprehensively identify germline SNVs, INDELs and CNVs from whole exome sequencing data of BRCA1/2 negative breast cancer patients.

In the rapidly evolving field of genomics, understanding the genetic basis of complex diseases like breast cancer, particularly its familial/hereditary forms, is crucial. Current methods often examine genomic variants-such as Single Nucleotide Variants (SNVs), insertions/deletions (Indels), and Copy Number Variations (CNVs)-separately, lacking an integrated approach. Here, we introduced a robust, flexible methodology for a comprehensive variants' analysis using Whole Exome Sequencing (WES) data. Our approach uniquely combines meticulous validation with an effective variant filtering strategy. By reanalyzing two germline WES datasets from BRCA1/2 negative breast cancer patients, we demonstrated our tool's efficiency and adaptability, uncovering both known and novel variants. This contributed new insights for potential diagnostic, preventive, and therapeutic strategies. Our method stands out for its comprehensive inclusion of key genomic variants in a unified analysis, and its practical resolution of technical challenges, offering a pioneering solution in genomic research. This tool presents a breakthrough in providing detailed insights into the genetic alterations in genomes, with significant implications for understanding and managing hereditary breast cancer.

Worse prognosis of KRAS c.35 G > A mutant metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx).

BACKGROUND: Prognosis of KRAS wild-type and mutant metastatic colorectal cancer (MCRC) patients (pts) treated with bevacizumab (BEV)-containing chemotherapy is not significantly different. Since specific KRAS mutations confer different aggressive behaviors, the prognostic role of prevalent KRAS mutations was retrospectively evaluated in MCRC pts treated with first line FIr-B/FOx, associating BEV to triplet chemotherapy. METHODS: Tumor samples were screened for KRAS codon 12, 13 and BRAF V600E mutations by SNaPshot and/or direct sequencing. MCRC pts <75-years-old were consecutively treated with FIr-B/FOx: weekly 12 hour-timed-flat-infusion/5-fluorouracil (900 mg/m(2) on days 1,2, 8, 9, 15, 16,22, 23), irinotecan plus BEV (160 mg/m(2) and 5 mg/kg, respectively, on days 1,15); and oxaliplatin (80 mg/m(2), on days 8,22). Pts were classified as liver-limited (L-L) and other/multiple metastatic (O/MM). Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test. RESULTS: Fifty-nine pts were evaluated at a median follow-up of 21.5 months. KRAS mutant pts: c.35 G > A, 15 (25.4%); c.35 G > T, 7 (11.8%); c.38 G > A, 3 (5%); other, 3 (5%). KRAS wild-type, 31 pts (52.7%). The objective response rate (ORR), PFS and OS were, respectively: c.35 G > A mutant, 71%, 9 months, 14 months; other than c.35 G > A mutants, 61%, 12 months, 39 months. OS was significantly worse in c.35 G > A pts compared to KRAS wild-type (P = 0.002), KRAS/BRAF wild-type (P = 0.03), other MCRC patients (P = 0.002), other than c.35 G > A (P = 0.05), other codon 12 (P = 0.03) mutant pts. OS was not significantly different compared to c.35 G > T KRAS mutant (P = 0.142). CONCLUSIONS: KRAS c.35 G > A mutant status may be significantly associated with a worse prognosis of MCRC pts treated with first line FIr-B/FOx intensive regimen compared to KRAS/BRAF wild type and other than c.35 G > A mutant pts.

Reverse-phase protein microarray highlights HER2 signaling activation in immunohistochemistry/FISH/HER2-negative breast cancers.

EVALUATION OF: Wulfkuhle JD, Berg D, Wolff C et al. Molecular analysis of HER2 signaling in human breast cancer by functional protein pathway activation mapping. Clin. Cancer Res. 18(23), 6426-6435 (2012). Exhaustive characterization and mapping of pivotal molecules and downstream effectors deregulated in breast cancer is of fundamental clinical value to define the most effective therapy. Wulfkuhle et al. applied reverse-phase protein microarray, a highly sensitive immunoassay able to perform quantitative and multiplexed analysis of total and/or modified cellular proteins, to assess protein levels and activation/phosphorylation status of the HER family (EGFR, HER2, HER3) and downstream signaling molecules in HER2(+) and HER2(-) breast cancers. The research was performed using laser capture microdissected tumor epithelial cells from frozen samples and formalin-fixed paraffin embedded specimens, which were also analyzed by immunohistochemistry (IHC) and FISH. This study identified a subgroup of IHC/FISH/HER2(-) patients with HER2 activation/phosphorylation levels comparable with those obtained from IHC/FISH/HER2(+) tumors. HER2 signaling activation was independent from total HER2 expression and involved HER3 and EGFR activation. These findings indicate that molecular characterization by reverse-phase protein microarray of HER2 and its partners/effectors in the signaling cascade enables the identification of a subgroup of IHC/FISH/HER2(-) patients showing HER2 signaling activation. These patients, currently excluded from targeted therapy administration, could potentially benefit from this and it could improve prognosis and survival.

Intranasal delivery of NGF rescues hearing impairment in aged SAMP8 mice.

Hearing loss impacts the quality of life and affects communication resulting in social isolation and reduced well-being. Despite its impact on society and economy, no therapies for age-related hearing loss are available so far. Loss of mechanosensory hair cells of the cochlea is a common event of hearing loss in humans. Studies performed in birds demonstrating that they can be replaced following the proliferation and transdifferentiation of supporting cells, strongly pointed out on HCs regeneration as the main focus of research aimed at hearing regeneration. Neurotrophins are growth factors involved in neuronal survival, development, differentiation, and plasticity. NGF has been involved in the interplay between auditory receptors and efferent innervation in the cochlea during development. During embryo development, both NGF and its receptors are highly expressed in the inner ears. It has been reported that NGF is implicated in the differentiation of auditory gangliar and hair cells. Thus, it has been proposed that NGF administration can decrease neuronal damage and prevent hearing loss. The main obstacle to the development of hearing impairment therapy is that efficient means of delivery for selected drugs to the cochlea are missing. Herein, in this study NGF was administered by the intranasal route. The first part of the study was focused on a biodistribution study, which showed the effective delivery in the cochlea; while the second part was focused on analyzing the potential therapeutic effect of NGF in senescence-accelerated prone strain 8 mice. Interestingly, intranasal administration of NGF resulted protective in counteracting hearing impairment in SAMP8 mice, ameliorating hearing performances (analyzed by auditory brainstem responses and distortion product otoacoustic emission) and hair cells morphology (analyzed by microscopy analysis). The results obtained were encouraging indicating that the neurotrophin NGF was efficiently delivered to the inner ear and that it was effective in counteracting hearing loss.

Role of the Molecular Tumor Board for the Personalized Treatment of Patients with Metastatic Breast Cancer: A Focus on the State of the Art in Italy.

Molecular tumor boards (MTBs) are multidisciplinary groups that combine molecular and clinical data from cancer patients in order to formulate treatment recommendations for precision medicine. To date, there is insufficient data to support the use of singleplex or next-generation sequencing (NGS) technologies to select first-line therapy for patients with metastatic breast cancer (MBC), but considering the high number of level II alterations, according to the ESMO scale for clinical actionability of molecular targets (ESCAT), it is suggested to include patients in molecular screening programs in order to be able to offer targeted therapies for specific genomic alterations. This article aims at reviewing the most recent literature related to the most used methodologies/approaches for molecular diagnostics and variants' classification, summarizing the internationally published molecular screening studies in support of MTB activity and, in the end, discussing MTBs' current position and role in Italy, the number of which is increasing, also thanks to the thrust of institutions.

Molecular Mechanisms Underpinning Immunometabolic Reprogramming: How the Wind Changes during Cancer Progression.

Metabolism and the immunological state are intimately intertwined, as defense responses are bioenergetically expensive. Metabolic homeostasis is a key requirement for the proper function of immune cell subsets, and the perturbation of the immune-metabolic balance is a recurrent event in many human diseases, including cancer, due to nutrient fluctuation, hypoxia and additional metabolic changes occurring in the tumor microenvironment (TME). Although much remains to be understood in the field of immunometabolism, here, we report the current knowledge on both physiological and cancer-associated metabolic profiles of immune cells, and the main molecular circuits involved in their regulation, highlighting similarities and differences, and emphasizing immune metabolic liabilities that could be exploited in cancer therapy to overcome immune resistance.

Targeting costimulatory molecules to improve antitumor immunity.

The full activation of T cells necessitates the concomitant activation of two signals, the engagement of T-cell receptor by peptide/major histocompatibility complex II and an additional signal delivered by costimulatory molecules. The best characterized costimulatory molecules belong to B7/CD28 and TNF/TNFR families and play crucial roles in the modulation of immune response and improvement of antitumor immunity. Unfortunately, tumors often generate an immunosuppressive microenvironment, where T-cell response is attenuated by the lack of costimulatory molecules on the surface of cancer cells. Thus, targeting costimulatory pathways represent an attractive therapeutic strategy to enhance the antitumor immunity in several human cancers. Here, latest therapeutic approaches targeting costimulatory molecules will be described.