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Key Points Circulating endothelial cells (CECs) with a mature phenotype, which are probably derived from blood vessel wall turnover, are increased in patients with some types of cancer and in various other conditions including mechanical, inflammatory, infective, ischaemic and autoimmune states. A subpopulation of CECs shows a progenitor-like phenotype. Preclinical and clinical data indicate that these circulating endothelial progenitors (CEPs) can incorporate in cancer vessels, albeit usually at low frequencies. Some preclinical studies suggest that CEPs have a key role in promoting cancer vasculogenesis and in late stages of cancer development. Therefore, CEP-targeting drugs (including many anti-angiogenic agents) might, in principle, inhibit cancer growth. CEC and CEP numbers, kinetics and viability can be measured by different approaches, including positive enrichment by immunobeads and flow cytometry. However, so far no single antigen has been successfully exploited to discriminate between endothelial and haematopoietic cells; consequently, a multiparametric investigation at the single-cell level is mandatory at present. CEC measurement has been found to correlate well with well-known preclinical assays of angiogenesis, such as the corneal micropocket assay, which cannot be adapted for use in patients. In addition, CEC kinetics and viability have been found to correlate with clinical outcomes in cancer patients treated with anti-angiogenic therapeutic approaches. CECs and/or CEPs might, in the future, be used to deliver drugs to cancer vessels. The number of circulating endothelial cells and their progenitors is increased in some types of cancer, and there is evidence that aspects of these cells might correlate with clinical outcome of cancer patients treated with anti-angiogenic drugs. Increases in the number of circulating endothelial cells (CECs) and progenitors (CEPs) have been reported in various pathological conditions including cancer. Preclinical studies have shown that CEC and CEP kinetics correlate well with several standard laboratory angiogenesis assays, which cannot be used in humans. At the clinical level, evidence is emerging that CEC kinetics and viability might correlate with clinical outcomes in cancer patients who undergo anti-angiogenic treatment. Therefore, CEC and CEP measurement has potential as a surrogate marker for monitoring anti-angiogenic treatment and drug activity, and could help to determine the optimal biological dose of anti-angiogenic drugs, which are being used with increasing frequency in medical oncology.

Non-small-cell lung carcinoma (NSCLC) is the most common lung cancer and one of the pioneer tumors in which immunotherapy has radically changed patients’ outcomes. However, several issues are emerging and their implementation is required to optimize immunotherapy-based protocols. In this work, we investigate the ability of the Bromodomain and Extra-Terminal protein inhibitors (BETi) to stimulate a proficient anti-tumor immune response toward NSCLC. By using in vitro, ex-vivo, and in vivo models, we demonstrate that these epigenetic drugs specifically enhance Natural Killer (NK) cell cytotoxicity. BETi down-regulate a large set of NK inhibitory receptors, including several immune checkpoints (ICs), that are direct targets of the transcriptional cooperation between the BET protein BRD4 and the transcription factor SMAD3. Overall, BETi orchestrate an epigenetic reprogramming that leads to increased recognition of tumor cells and the killing ability of NK cells. Our results unveil the opportunity to exploit and repurpose these drugs in combination with immunotherapy. Combination of BET inhibitors (BETi) with immunotherapy has been reported to be synergic for the treatment of non-small cell lung carcinoma (NSCLC). Here, the authors show that BETi-induced epigenetic reprogramming downregulates the expression of NK cell inhibitory receptors on NK cells, increasing their activation and cytotoxicity against NSCLC.

The role of innate lymphoid cells (ILCs), including natural killer (NK) cells, is pivotal in inflammatory modulation and cancer. Natural killer cell activity and count have been demonstrated to be regulated by the expression of activating and inhibitory receptors together with and as a consequence of different stimuli. The great majority of NK cell populations have an anti-tumor activity due to their cytotoxicity, and for this reason have been used for cellular therapies in cancer patients. On the other hand, the recently classified helper ILCs are fundamentally involved in inflammation and they can be either helpful or harmful in cancer development and progression. Tissue niche seems to play an important role in modulating ILC function and conversion, as observed at the transcriptional level. In the past, these cell populations have been classified by the presence of specific cellular receptor markers; more recently, due to the advent of single-cell RNA sequencing (scRNA-seq), it has been possible to also explore them at the transcriptomic level. In this article we review studies on ILC (and NK cell) classification, function and their involvement in cancer. We also summarize the potential application of NK cells in cancer therapy and give an overview of the most recent studies involving ILCs and NKs at scRNA-seq, focusing on cancer. Finally, we provide a resource for those who wish to start single-cell transcriptomic analysis on the context of these innate lymphoid cell populations.

We report the case of a 51-year-old male patient initially diagnosed with JAK2-V617F-mutated polycythemia vera (PV), who developed chronic phase BCR::ABL1-positive chronic myeloid leukemia (CML) 11 years later. The patient was treated with hydroxyurea and later with ruxolitinib (RUX) for PV. Following CML diagnosis, treatment with imatinib combined with RUX was initiated. Imatinib and RUX combination therapy proved to be safe and well-tolerated without major adverse events. After over one year of treatment, the patient maintained a complete cytogenetic response and a MR 2 molecular response. Imatinib was switched to dasatinib due to the unsatisfying molecular response achieved. This case highlights the uncommon coexistence of JAK2 mutation and BCR::ABL1 translocation and supports the feasibility and safety of combining JAK2 inhibitors and tyrosine kinase inhibitors in such scenarios.

Acute myeloid leukemia (AML) is an aggressive disease with a high relapse rate. In this study, we map the metabolic profile of CD34 + (CD38 low/- ) AML cells and the extracellular vesicle signatures in circulation from AML patients at diagnosis. CD34 + AML cells display high antioxidant glutathione levels and enhanced mitochondrial functionality, both associated with poor clinical outcomes. Although CD34 + AML cells are highly dependent on glucose oxidation and glycolysis for energy, those from intermediate- and adverse-risk patients reveal increased mitochondrial dependence. Extracellular vesicles from AML are mainly enriched in stem cell markers and express antioxidant GPX3, with their profiles showing potential prognostic value. Extracellular vesicles enhance mitochondrial functionality and dependence on CD34 + AML cells via the glutathione/GPX4 axis. Notably, extracellular vesicles from adverse-risk patients enhance leukemia cell engraftment in vivo. Here, we show a potential noninvasive approach based on liquid ‘cell-extracellular vesicle’ biopsy toward a redefined metabolic stratification in AML. The role of metabolism in acute myeloid leukaemia (AML) onset remains to be explored. Here, the authors explore the metabolic landscape of AML cells and the signature of extracellular vesicles (EVs) in peripheral blood and show that circulating EVs regulate leukaemia (stem) cell metabolic reprogramming.

Leukemic cells proliferate faster than non-transformed counterparts. This requires them to change their metabolism to adapt to their high growth. This change can stress cells and facilitate recognition by immune cells such as cytotoxic lymphocytes, which express the activating receptor Natural Killer G2-D (NKG2D). The tumor suppressor gene p53 regulates cell metabolism, but its role in the expression of metabolism-induced ligands, and subsequent recognition by cytotoxic lymphocytes, is unknown. We show here that dichloroacetate (DCA), which induces oxidative phosphorylation (OXPHOS) in tumor cells, induces the expression of such ligands, e.g. MICA/B, ULBP1 and ICAM-I, by a wtp53-dependent mechanism. Mutant or null p53 have the opposite effect. Conversely, DCA sensitizes only wtp53-expressing cells to cytotoxic lymphocytes, i.e. cytotoxic T lymphocytes and NK cells. In xenograft in vivo models, DCA slows down the growth of tumors with low proliferation. Treatment with DCA, monoclonal antibodies and NK cells also decreased tumors with high proliferation. Treatment of patients with DCA, or a biosimilar drug, could be a clinical option to increase the effectiveness of CAR T cell or allogeneic NK cell therapies.

Disease relapse caused by drug resistance still represents a major clinical hurdle in cancer treatments. Tumor cells may take advantage of different intracellular and genetic systems attenuating the drug effects. Resistant cells or minimal residual disease (MRD) cells have strong clinical relevance, as they might give rise to secondary tumors when the therapy is concluded. Thus, MRDs are crucial therapeutic targets in order to prevent tumor relapse. Therefore, several groups aim at understanding how MRDs are orginated, characterizing their molecular features, and eradicating them. In this review, we will describe MRD from a genetic, evolutionary, and molecular point of view. Moreover, we will focus on the new in vitro, in vivo, preclinical, and clinical studies that aim at eradicating tumor resistance.

Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The anti-diabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of anti-apoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.

Background High-grade breast cancer (HGBC) is an aggressive disease with poor prognosis, underscoring the need for new treatment strategies. The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a pivotal role in tumor progression, therapy resistance, and immune regulation. An ECM-related gene signature (defined ECM3), found in approximately 35% of HGBC cases, is associated with aggressive tumors, epithelial-to-mesenchymal transition (EMT), poor clinical outcome and increased infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs). Methods In this study, we investigated the impact of the ECM on T cell regulation in HGBC patients, focusing on the relationship between ECM3 + tumors and T cell phenotypes. We employed mouse models to dissect the molecular mechanisms linking ECM components to T cell regulation, with particular attention to the role of the matricellular protein SPARC, a key component of the ECM3 signature. Results We revealed a significant correlation between highly suppressive programmed cell death-1 (PD-1) negative regulatory T cells (Tregs) and ECM3 + tumors. In mouse models, SPARC was found to down-regulate PD-1 on Tregs by promoting IL-23 release, which in turn induced SATB1 expression, a repressor of the pdcd1 gene. The selective expression of the IL-23 receptor on Tregs accounted for the targeted effect of IL-23 on these cells. Notably, blocking IL-23 with monoclonal antibodies restored PD-1 expression on Tregs and activated T effector cells. Conclusion These findings extend the immune-regulatory role of the ECM to include regulatory T cells and identify potential new therapeutic targets for high-grade breast cancers. Moreover, they highlight ECM3 as a potential biomarker of resistance to PD-1/PD-L1 immune checkpoint blockade (ICB), suggesting that ECM3⁺ patients may benefit from alternative checkpoint inhibitor therapies beyond PD-1/PD-L1. Graphical Abstract A qPCR analysis of 8 genes was used to determine the ECM3 status in HGBC patients. The immunoprofile of circulating PBMCs revealed an enrichment of highly suppressive PD-1⁻ regulatory T cells in ECM3⁺ patients. Using murine models, we elucidated the mechanism linking ECM3 to PD-1⁻ Tregs: SPARC, a gene within the ECM3 signature, induces IL-23 in the tumor microenvironment. Through its cognate receptor, IL-23 promotes the transcription factor SATB1 in Tregs, which mediates the repression of PD-1.

Hypomethylating agents are a classical frontline low-intensity therapy for older patients with acute myeloid leukemia. Recently, TP53 gene mutations have been described as a potential predictive biomarker of better outcome in patients treated with a ten-day decitabine regimen., However, functional characteristics of TP53 mutant are heterogeneous, as reflected in multiple functional TP53 classifications and their impact in patients treated with azacitidine is less clear. We analyzed the therapeutic course and outcome of 279 patients treated with azacitidine between 2007 and 2016, prospectively enrolled in our regional healthcare network. By screening 224 of them, we detected TP53 mutations in 55 patients (24.6%), including 53 patients (96.4%) harboring high-risk cytogenetics. The identification of any TP53 mutation was associated with worse overall survival but not with response to azacitidine in the whole cohort and in the subgroup of patients with adverse karyotype. Stratification of patients according to three recent validated functional classifications did not allow the identification of TP53 mutated patients who could benefit from azacitidine. Systematic TP53 mutant classification will deserve further exploration in the setting of patients treated with conventional therapy and in the emerging field of therapies targeting TP53 pathway.