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Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

BackgroundImmune exhaustion and senescence are dominant dysfunctional states of effector T cells and major hurdles for the success of cancer immunotherapy. In the current study, we characterized how acute myeloid leukemia (AML) promotes the generation of senescent-like CD8+ T cells and whether they have prognostic relevance.METHODSWe analyzed NanoString, bulk RNA-Seq and single-cell RNA-Seq data from independent clinical cohorts comprising 1,896 patients treated with chemotherapy and/or immune checkpoint blockade (ICB).ResultsWe show that senescent-like bone marrow CD8+ T cells were impaired in killing autologous AML blasts and that their proportion negatively correlated with overall survival (OS). We defined what we believe to be new immune effector dysfunction (IED) signatures using 2 gene expression profiling platforms and reported that IED scores correlated with adverse-risk molecular lesions, stemness, and poor outcomes; these scores were a more powerful predictor of OS than 2017-ELN risk or leukemia stem cell (LSC17) scores. IED expression signatures also identified an ICB-unresponsive tumor microenvironment and predicted significantly shorter OS.ConclusionThe IED scores provided improved AML-risk stratification and could facilitate the delivery of personalized immunotherapies to patients who are most likely to benefit.TRIAL REGISTRATIONClinicalTrials.gov; NCT02845297.FUNDINGJohn and Lucille van Geest Foundation, Nottingham Trent University's Health & Wellbeing Strategic Research Theme, NIH/NCI P01CA225618, Genentech-imCORE ML40354, Qatar National Research Fund (NPRP8-2297-3-494).

The tumor immune contexture plays a major role for the clinical outcome of patients. High densities of CD45RO T helper 1 cells and CD8 T cells are associated with improved survival of patients with various cancer entities. In contrast, a higher frequency of tumor-infiltrating M2 macrophages is correlated with poor prognosis. Recent studies provide evidence that the tumor immune architecture also essentially contributes to the clinical efficacy of immune checkpoint inhibitor (CPI) therapy in patients. Pretreatment melanoma samples from patients who experienced a clinical response to anti-programmed cell death protein 1 (PD-1) treatment show higher densities of infiltrating CD8 T cells compared to samples from patients that progressed during therapy. Anti-PD-1 therapy results in an increased density of tumor-infiltrating T lymphocytes in treatment responders. In addition, elevated frequencies of melanoma-infiltrating TCF7 CD8 T cells are correlated with beneficial clinical outcome of anti-PD-1-treated patients. In contrast, a high density of tumor-infiltrating, dysfunctional PD-1 CD38 CD8 cells in melanoma patients is associated with anti-PD-1 resistance. Such findings indicate that comprehensive tumor immune contexture profiling prior to and during CPI therapy may lead to the identification of underlying mechanisms for treatment response or resistance, and the design of improved immunotherapeutic strategies. Here, we focus on studies exploring the impact of intratumoral T and B cells at baseline on the clinical outcome of CPI-treated cancer patients. In addition, recent findings demonstrating the influence of CPIs on tumor-infiltrating lymphocytes are summarized.

The Triggering Receptors Expressed on Myeloid cells (TREM) are a family of cell-surface molecules that control inflammation, bone homeostasis, neurological development and blood coagulation. TREM-1 and TREM-2, the best-characterized receptors so far, play divergent roles in several infectious diseases. In the intestine, TREM-1 is highly expressed by macrophages, contributing to inflammatory bowel disease (IBD) pathogenesis. Contrary to current understanding, TREM-2 also promotes inflammation in IBD by fueling dendritic cell functions. This review will focus specifically on recent insights into the role of TREM proteins in IBD development, and discuss opportunities for novel treatment approaches.

Hypoxia is a condition characterized by insufficient tissue oxygenation, which results in impaired oxidative energy production. A reduction in cellular oxygen levels induces the stabilization of hypoxia inducible factor α (HIF-1α), master regulator of the molecular response to hypoxia, involved in maintaining cellular homeostasis and driving hypoxic adaptation through the control of gene expression. Due to its high energy requirement, the brain is particularly vulnerable to oxygen shortage. Thus, hypoxic injury can cause significant metabolic changes in neural cell populations, which are associated with neurodegeneration. Recent evidence suggests that regulating HIF-1α may ameliorate the cellular damage in neurodegenerative diseases. Indeed, the hypoxia/HIF-1α signaling pathway has been associated to several processes linked to Parkinson’s disease (PD) including gene mutations, risk factors and molecular pathways such as mitochondrial dysfunction, oxidative stress and protein degradation impairment. This review will explore the impact of hypoxia and HIF-1α signaling on these specific molecular pathways that influence PD development and will evaluate different novel neuroprotective strategies involving HIF-1α stabilization.

Multiple myeloma (MM) is a plasma cell malignancy associated with high levels of monoclonal (M) protein in the blood and/or serum. MM can occur de novo or evolve from benign monoclonal gammopathy of undetermined significance (MGUS). Current translational research into MM focuses on the development of combination therapies directed against molecularly defined targets and that are aimed at achieving durable clinical responses. MM cells have a unique ability to evade immunosurveillance through several mechanisms including, among others, expansion of regulatory T cells (Treg), reduced T-cell cytotoxic activity and responsiveness to IL-2, defects in B-cell immunity, and induction of dendritic cell (DC) dysfunction. Immune defects could be a major cause of failure of the recent immunotherapy trials in MM. This article summarizes our current knowledge on the molecular determinants of immune evasion in patients with MM and highlights how these pathways can be targeted to improve patients' clinical outcome.

Background Tumor cells have evolved complex strategies to escape immune surveillance, a process which involves NK cells and T lymphocytes, and various immunological factors. Indeed, tumor cells recruit immunosuppressive cells [including regulatory T-cells (Treg), myeloid-derived suppressor cells (MDSC)] and express factors such as PD-L1. Molecularly targeted therapies, such as imatinib, have off-target effects that may influence immune function. Imatinib has been shown to modulate multiple cell types involved in anti-cancer immune surveillance, with potentially detrimental or favorable outcomes. Imatinib and other tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) have dramatically changed disease course. Our study aimed to characterize the different populations of the immune system in patients with CML affected by their treatment. Methods Forty-one patients with CML [33 treated with TKIs and 8 with TKIs plus interferon (IFN)-α] and 20 controls were enrolled in the present study. Peripheral blood populations of the immune system [referred to as the overview of immune system (OVIS) panel, Treg cells and MDSCs] and PD-1 expression were evaluated by flow cytometry. The immunological profile was assessed using the mRNA Pan-Cancer Immune Profiling Panel and a NanoString nCounter FLEX platform. Results Patients receiving combination therapy (TKIs + IFN-α) had lower numbers of lymphocytes, particularly T cells [838/µL (95% CI 594–1182)] compared with healthy controls [1500/µL (95% CI 1207 – 1865), p = 0.017]. These patients also had a higher percentage of Treg (9.1%) and CD4 + PD-1 + cells (1.65%) compared with controls [Treg (6.1%) and CD4 + /PD-1 + (0.8%); p ≤ 0.05]. Moreover, patients treated with TKIs had more Mo-MDSCs (12.7%) whereas those treated with TKIs + IFN-α had more Gr-MDSC (21.3%) compared to controls [Mo-MDSC (11.4%) and Gr-MDSC (8.48%); p ≤ 0.05]. CD56 bright NK cells, a cell subset endowed with immune-regulatory properties, were increased in patients receiving TKIs plus IFN-α compared with those treated with TKIs alone. Interestingly, serum IL-21 was significantly lower in the TKIs plus IFN-α cohort. Within the group of patients treated with TKI monotherapy, we observed that individuals receiving 2nd generation TKIs had lower percentages of CD4 + Treg (3.63%) and Gr-MDSC (4.2%) compared to patients under imatinib treatment (CD4 + Treg 6.18% and Gr-MDSC 8.2%), but higher levels of PD-1-co-expressing CD4 + cells (1.92%). Conclusions Our results suggest that TKIs in combination with IFN-α may promote an enhanced immune suppressive state.

Interactions between the immune system and tumors are highly reciprocal in nature, leading to speculation that tumor recurrence or therapeutic resistance could be influenced or predicted by immune events that manifest locally, but can be detected systemically. Multi-parameter flow cytometry was used to examine the percentage and phenotype of natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs), monocyte subsets and regulatory T (Treg) cells in the peripheral blood of of 85 patients with breast cancer (50 of whom were assessed before and after one cycle of anthracycline-based chemotherapy), and 23 controls. Transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) in 23 patients were generated using a NanoString gene profiling platform. An increased percentage of immunosuppressive cells such as granulocytic MDSCs, intermediate CD14 CD16 monocytes and CD127 CD25 FoxP3 Treg cells was observed in patients with breast cancer, especially patients with stage 3 and 4 disease, regardless of ER status. Following neoadjuvant chemotherapy, B cell numbers decreased significantly, whereas monocyte numbers increased. Although chemotherapy had no effect on the percentage of Treg, MDSC and NK cells, the expression of inhibitory receptors CD85j, LIAR and NKG2A and activating receptors NKp30 and NKp44 on NK cells increased, concomitant with a decreased expression of NKp46 and DNAM-1 activating receptors. Transcriptomic profiling revealed a distinct group of 3 patients in the triple negative breast cancer (TNBC) cohort who expressed high levels of mRNA encoding genes predominantly involved in inflammation. The analysis of a large transcriptomic dataset derived from the tumors of patients with TNBC revealed that the expression of predicted relapse-free survival. The peripheral blood immunome of patients with breast cancer is influenced by the presence and stage of cancer, but not by molecular subtypes. Furthermore, immune profiling coupled with transcriptomic analyses of peripheral blood cells may identify patients with TNBC that are at risk of relapse after chemotherapy.

Patients with treatment refractory Crohn's disease (CD) suffer debilitating symptoms, poor quality of life, and reduced work productivity. Surgery to resect inflamed and fibrotic intestine may mandate creation of a stoma and is often declined by patients. Such patients continue to be exposed to medical therapy that is ineffective, often expensive and still associated with a burden of adverse effects. Over the last two decades, autologous hematopoietic stem cell transplantation (auto-HSCT) has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies have provided proof of concept that auto-HSCT can restore immunological tolerance in chronic autoimmunity the eradication of pathological immune responses and a profound reconfiguration of the immune system. Herein, we review current experience of auto-HSCT for the treatment of CD as well as approaches that have been used to monitor immune reconstitution following auto-HSCT in patients with ADs, including CD. We also detail immune reconstitution studies that have been integrated into the randomized controlled Autologous Stem cell Transplantation In refractory CD-Low Intensity Therapy Evaluation trial, which is designed to test the hypothesis that auto-HSCT using reduced intensity mobilization and conditioning regimens will be a safe and effective means of inducing sustained control in refractory CD compared to standard of care. Immunological profiling will generate insight into the pathogenesis of the disease, restoration of responsiveness to anti-TNF therapy in patients with recurrence of endoscopic disease and immunological events that precede the onset of disease in patients that relapse after auto-HSCT.

BackgroundAllogeneic double-negative T-cell (DNT) therapy has emerged as a novel, off-the-shelf cellular treatment with clinical feasibility, safety, and promising efficacy against leukemia. However, the biology of DNTs is less well characterized, and how DNT therapy distinguishes from conventional γδ T-cell therapy remains unclear. Collectively, this hinders our ability to bolster DNT functionalities in cancer therapy. Here, we performed single-cell RNA sequencing with in vitro and in vivo functional analysis on DNTs. As a significant proportion of DNTs express Vγ9Vδ2 (Vδ2) TCR chain, we compared DNTs with donor-matched conventional Vδ2 T cells expanded with zoledronic acid.MethodsHealthy donor-derived allogeneic DNTs and Vδ2 T cells were expanded ex vivo. Single-cell RNA sequencing analysis was performed on both cellular products to identify the transcriptional landscape and inferred cellular interactions within DNTs, followed by comparisons with donor-matched Vδ2 T cells. Unique cellular subsets found only in DNTs were depleted to identify their contributions to the overall efficacy of DNTs against acute myeloid leukemia. The anti-leukemic activity and in vivo persistence of DNTs and Vδ2 T-cells were explored using flow cytometry-based cytotoxicity assays, memory phenotyping, and xenograft models.ResultsDespite a shared Vδ2 expression between cellular products, we identified unique cellular compositions in DNTs that contribute to distinct transcriptional and cellular communication patterns relative to the donor-matched Vδ2 T cells, including higher expression of genes identified in chimeric antigen receptor T cells that persist in patients with durable cancer-remission. Vδ2– DNTs exhibited strong persistence characteristics, and their presence promoted the cytotoxic capabilities of Vδ2+ DNTs in repeated stimulation assays. This unique genetic signature and diverse cellular composition of DNTs resulted in better overall ex vivo expansion, prolonged persistence, and superior anti-leukemic activity compared with Vδ2 T cells in vitro and in vivo.ConclusionsThese results highlight the unique transcriptional, cellular, and functional profile of human DNTs and support the continued clinical investigation of allogeneic DNT therapy. The data also provide a reference gene signature that may help improve the efficacy of other types of allogeneic adoptive cellular therapies.