The Role of Innate and Adaptive Immune Cells in the Pathogenesis and Development of the Inflammatory Response in Ulcerative Colitis

Ulcerative colitis (UC) is a chronic inflammatory disease with an underlying excessive immune response directed against resident microbiota and/or dietary antigens. Both innate and adaptive immune cells play a crucial role in the pathogenesis of UC. In the case of innate immune response cells, neutrophils, dendritic cells, macrophages have a crucial impact on the development of the disease, as well as innate lymphoid cells, which have received a particular attention in recent years. On the other hand, mechanisms of the adaptive immune response involve cells such as: cytotoxic lymphocytes, regulatory lymphocytes Treg, or helper lymphocytes Th–Th2, Th9, Th17, Th22, among which significant discoveries about Th9 and Th17 lymphocytes have been made in recent years. Due to the presence of antibodies directed against resident microbiota or one’s own tissues, the influence of B lymphocytes on the development of UC is also highlighted. Additionally, the impact of cytokines on shaping the immune response as well as sustaining inflammation seems to be crucial. This review briefly describes the current state of knowledge about the involvement of the innate and adaptive immune systems in the pathogenesis of UC. The review is based on personal selection of literature that were retrieved by a selective search in PubMed using the terms “ulcerative colitis” and “pathogenesis of ulcerative colitis”. It included systematic reviews, meta-analyses and clinical trials. Our knowledge of the involvement of the immune system in the pathophysiology of IBD has advanced rapidly over the last two decades, leading to the development of several immune-targeted treatments with a biological source, known as biologic agents.

Immune-Mediated Effects of Microplanar Radiotherapy with a Small Animal Irradiator

Spatially fractionated radiotherapy has been shown to have effects on the immune system that differ from conventional radiotherapy (CRT). We compared several aspects of the immune response to CRT relative to a model of spatially fractionated radiotherapy (RT), termed microplanar radiotherapy (MRT). MRT delivers hundreds of grays of radiation in submillimeter beams (peak), separated by non-radiated volumes (valley). We have developed a preclinical method to apply MRT by a commercial small animal irradiator. Using a B16-F10 murine melanoma model, we first evaluated the in vitro and in vivo effect of MRT, which demonstrated significant treatment superiority relative to CRT. Interestingly, we observed insignificant treatment responses when MRT was applied to Rag−/− and CD8-depleted mice. An immuno-histological analysis showed that MRT recruited cytotoxic lymphocytes (CD8), while suppressing the number of regulatory T cells (Tregs). Using RT-qPCR, we observed that, compared to CRT, MRT, up to the dose that we applied, significantly increased and did not saturate CXCL9 expression, a cytokine that plays a crucial role in the attraction of activated T cells. Finally, MRT combined with anti-CTLA-4 ablated the tumor in half of the cases, and induced prolonged systemic antitumor immunity.

Co-Stimulatory Molecules during Immune Control of Epstein Barr Virus Infection

The Epstein Barr virus (EBV) is one of the prominent human tumor viruses, and it is efficiently immune-controlled in most virus carriers. Cytotoxic lymphocytes strongly expand during symptomatic primary EBV infection and in preclinical in vivo models of this tumor virus infection. In these models and patients with primary immunodeficiencies, antibody blockade or deficiencies in certain molecular pathways lead to EBV-associated pathologies. In addition to T, NK, and NKT cell development, as well as their cytotoxic machinery, a set of co-stimulatory and co-inhibitory molecules was found to be required for EBV-specific immune control. The role of CD27/CD70, 4-1BB, SLAMs, NKG2D, CD16A/CD2, CTLA-4, and PD-1 will be discussed in this review. Some of these have just been recently identified as crucial for EBV-specific immune control, and for others, their important functions during protection were characterized in in vivo models of EBV infection and its immune control. These insights into the phenotype of cytotoxic lymphocytes that mediate the near-perfect immune control of EBV-associated malignancies might also guide immunotherapies against other tumors in the future.

Metformin Sensitizes Leukemic Cells to Cytotoxic Lymphocytes by Increasing Expression of Intercellular Adhesion Molecule-1 (ICAM-1)

Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The antidiabetic 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 antiapoptotic 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.

Phospho-proteomics reveals that RSK signaling is required for proliferation of natural killer cells stimulated with IL-2 or IL-15

Natural killer (NK) cells are cytotoxic lymphocytes that play a critical role in the innate immune system. Although cytokine signaling is crucial for the development, expansion, and cytotoxicity of NK cells, the signaling pathways stimulated by cytokines are not well understood. Here, we sought to compare the early signaling dynamics induced by the cytokines interleukin (IL)-2 and IL-15 using liquid chromatography-mass spectrometry (LC-MS)-based phospho-proteomics. Following stimulation of the immortalized NK cell line NK-92 with IL-2 or IL-15 for 5, 10, 15, or 30 minutes, we identified 8,692 phospho-peptides from 3,023 proteins. Comparing the kinetic profiles of 3,619 fully quantified phospho-peptides, we found that IL-2 and IL-15 induced highly similar signaling in NK-92 cells. Among the IL-2/IL-15-regulated phospho-sites were both well-known signaling events like the JAK/STAT pathway and novel signaling events with potential functional significance including LCP1 Ser5, PAK2 Ser141, and STK17B Ser12. Using bioinformatic approaches, we sought to identify kinases regulated by IL-2/IL-15 stimulation and found that the p90 ribosomal S6 kinase (p90RSK) family was activated by both cytokines. Using pharmacological inhibitors, we then discovered that RSK signaling is required for IL-2 and IL-15-induced proliferation in NK-92 cells. Taken together, our analysis represents the first phospho-proteomic characterization of cytokine signaling in NK cells and increases our understanding of how cytokine signaling regulates NK cell function.

What Is the Role of HLA-I on Cancer Derived Extracellular Vesicles? Defining the Challenges in Characterisation and Potential Uses of This Ligandome

The Human Leukocyte Antigen class I (HLA-I) system is an essential part of the immune system that is fundamental to the successful activation of cytotoxic lymphocytes, and an effective subsequent immune attack against both pathogen-infected and cancer cells. The importance of cytotoxic T cell activity and ability to detect foreign cancer-related antigenic peptides has recently been highlighted by the successful application of monoclonal antibody-based checkpoint inhibitors as novel immune therapies. Thus, there is an increased interest in fully characterising the repertoire of peptides that are being presented to cytotoxic CD8+ T cells by cancer cells. However, HLA-I is also known to be present on the surface of extracellular vesicles, which are released by most if not all cancer cells. Whilst the peptide ligandome presented by cell surface HLA class I molecules on cancer cells has been studied extensively, the ligandome of extracellular vesicles remains relatively poorly defined. Here, we will describe the current understanding of the HLA-I peptide ligandome and its role on cancer-derived extracellular vesicles, and evaluate the aspects of the system that have the potential to advance immune-based therapeutic approaches for the effective treatment of cancer.

Immune Combination Therapy With NK Cell and Pembrolizumab Showed Therapeutic Efficacy in Treating Advanced Solid Tumors

Background：Natural killer cells are innate cytotoxic lymphocytes that play an important role in the anti-tumor immune response. However, in the microenvironment of solid tumors, the effector functions of NK cells are often impaired by the induction of immune checkpoint inhibitors, including PD-1. Methods: In this study, we conducted a two-phase study treating advanced solid patients with NK cell therapy (phase 1) or NK and anti-PD-1 inhibitor, pembrolizumab (phase 2).Results: After treatment, only 3 of 9 patients achieved stable disease after accepting NK cell therapy in the phase 1 study. While in the phase 2 study, 4 patients achieved stable diseases and 1 patient achieved partial response. Remarkably, no severe adverse event was observed in patients treated by NK cell and pembrolizumab combination therapy.Conclusion: The results in our study indicated that immune combination therapy with NK cell and pembrolizumab might be a promising and safe approaches to treating advanced solid tumors.

Single-cell multiomics reveals increased plasticity, resistant populations and stem-cell-like blasts in KMT2A-rearranged leukemia

KMT2A-rearranged (KMT2A-r) infant ALL is a devastating malignancy with a dismal outcome, and younger age at diagnosis is associated with increased risk of relapse. To discover age-specific differences and critical drivers that mediate poor outcome in KMT2A-r ALL, we subjected KMT2A-r leukemias and normal hematopoietic cells from patients of different ages to single cell multi-omics analyses. We uncovered the following critical new insights: leukemia cells from patients younger than 6 months have significantly increased lineage plasticity. Steroid response pathways are downregulated in the most immature blasts from younger patients. We identify a hematopoietic stem and progenitor-like (HSPC-like) population in the blood of younger patients that contains leukemic blasts and form an immunosuppressive signaling circuit with cytotoxic lymphocytes. These observations offer a compelling explanation for the ability of leukemias in young patients to evade chemotherapy and immune mediated control. Our analysis also revealed pre-existing lymphomyeloid primed progenitors and myeloid blasts at initial diagnosis of B-ALL. Tracking of leukemic clones in two patients whose leukemia underwent a lineage switch documented the evolution of such clones into frank AML. These findings provide critical insights into KMT2A-r ALL and have clinical implications for molecularly targeted and immunotherapy approaches. Beyond infant ALL, our study demonstrates the power of single cell multi-omics to detect tumor intrinsic and extrinsic factors affecting rare but critical subpopulations within a malignant population that ultimately determines patient outcome.

Adhesion concept in cancer biology: local and central mechanisms (part 2)

The review presents the concept the key mechanism of the tumor process is a violation of adhesion interactions involving local and central mechanisms. Local features of adhesive dysregulation are demonstrated in the part 1. The second part describes the central processes. Features of local adhesive dysregulation which provides the main properties of the tumor (loss of tissue control of proliferation, anaplasia, invasion, metastasis, lack of immunological surveillance) can be controlled by central mechanisms involving the dopaminergic system which is able using immunoadhesional interactions to regulate the active phase of immune responses against the tumor interfering the process and thus interrupting the development of a malignant neoplasm initiated by a local mutation in the target tissue. The proposed concept of the adhesion key role dysregulation in the target tissue neoplasia and the processes of immunoreactivity involving the loss of central dopamine as an adhesive-damaging factor at the level of immune responses reveals among other things the stress mechanism of cancer etiology. At the same time, the central dopamine directly affects the level of dopamine in the peripheral body. The main reserves of peripheral dopamine in platelets and blood lymphocytes can serve as a guarantee of antitumor protection. Being the production of lymphocytes peripheral dopamine plays a role in the maturation of cytotoxic lymphocytes promoting their migration to tumor nodes, the formation of conjugates with tumor cells. So, dopamine participates in the active phase of immune responses against the tumor contributing to the support of adhesive interactions between immune effectors and target cells. The latter also helps to protect the body from tumor diseases which obviously shorten life.The adhesive concept of local and central control of tumor formation creates a certain perspective for improving the effectiveness of diagnosticis, prevention and treatment methods which can be a step towards solving the problem of malignant neoplasms.

Altered expressions of CXCR4 and CD26 on T-helper lymphocytes in hereditary hemorrhagic telangiectasia

Background Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by a deregulated neo-angiogenesis. Besides a mainly vascular phenotype (muco-cutaneous telangiectases, arteriovenous malformations), a specific risk of infection is suggested by case series of severe and atypical infections as well as by reports of decreased T and natural killer (NK) lymphocyte counts. As some evidence supports a dysregulation of the CXCR4/CXCL12 chemotactic axis of HHT endothelial cells, we hypothesized that a similar phenomenon could occur on lymphocytes. Methods Eighteen HHT patients with history of severe infection (HSI) were matched in age and sex with 18 HHT without HSI and 18 healthy control subjects (HC). We assessed the cell count and the surface expression of CXCR4 and CD26 (CXCL12 inactivating peptidase) of circulating T-helper and T-cytotoxic lymphocytes (including naive, memory and activated subsets) and NK cells. Results The overall HHT group of 36 patients exhibited a reduction of circulating T-helper lymphocytes compared to HC (median: 517 vs. 1026 cells/mm3, p < 0.0001), correlated with age (r = − 0.46, p = 0.005), requirement of intravenous iron or blood transfusions (median: 291 vs. 627 cells/mm3, p = 0.03) and CXCR4 surface expression (r = 0.353, p = 0.0345). CXCR4 and CD26 membrane expression were both decreased on HHT T-helper lymphocytes (median MFI ratio: 4.49 vs. 5.74 for CXCR4 and 3.21 vs. 4.33 for CD26, p = 0.03 and 0.0018 respectively) with an unchanged CXCR4/CD26 ratio. The HHT group with HSI had a higher CXCR4/CD26 ratio on the total T-lymphocyte population, as well as on the T-helper population and its naive subset (median on naive T-helper cells: 2.34 vs. 1.32, p = 0.0002). Conclusions Our findings support a dysregulation of the CXCL12/CXCR4 chemotaxis of T-helper lymphocytes in HHT patients, potentially linked to their T-helper lymphopenia and susceptibility to infection.