Background: The skeletal muscle reconstruction occurs thanks to unipotent stem cells, i.e., satellite cells. The satellite cells remain quiescent and localized between myofiber sarcolemma and basal lamina. They are activated in response to muscle injury, proliferate, differentiate into myoblasts, and recreate myofibers. The stem and progenitor cells support skeletal muscle regeneration, which could be disturbed by extensive damage, sarcopenia, cachexia, or genetic diseases like dystrophy. Many lines of evidence showed that the level of oxygen regulates the course of cell proliferation and differentiation. Methods: In the present study, we analyzed hypoxia impact on human and pig bone marrow-derived mesenchymal stromal cell (MSC) and mouse myoblast proliferation, differentiation, and fusion. Moreover, the influence of the transplantation of human bone marrow-derived MSCs cultured under hypoxic conditions on skeletal muscle regeneration was studied. Results: We showed that bone marrow-derived MSCs increased VEGF expression and improved myogenesis under hypoxic conditions in vitro. Transplantation of hypoxia preconditioned bone marrow-derived MSCs into injured muscles resulted in the improved cell engraftment and formation of new vessels. Conclusions: We suggested that SDF-1 and VEGF secreted by hypoxia preconditioned bone marrow-derived MSCs played an essential role in cell engraftment and angiogenesis. Importantly, hypoxia preconditioned bone marrow-derived MSCs more efficiently engrafted injured muscles; however, they did not undergo myogenic differentiation.

Despite the unquestionable success achieved by rituximab-based regimens in the management of diffuse large B-cell lymphoma (DLBCL), the high incidence of relapsed/refractory disease still remains a challenge. The widespread clinical use of chemo-immunotherapy demonstrated that it invariably leads to the induction of resistance; however, the molecular mechanisms underlying this phenomenon remain unclear. Rituximab-mediated therapeutic effect primarily relies on complement-dependent cytotoxicity and antibody-dependent cell cytotoxicity, and their outcome is often compromised following the development of resistance. Factors involved include inherent genetic characteristics and rituximab-induced changes in effectors cells, the role of ligand/receptor interactions between target and effector cells, and the tumor microenvironment. This review focuses on summarizing the emerging advances in the understanding of the molecular basis responsible for the resistance induced by various forms of immunotherapy used in DLBCL. We outline available models of resistance and delineate solutions that may improve the efficacy of standard therapeutic protocols, which might be essential for the rational design of novel therapeutic regimens.

Immunotherapy revolutionized cancer treatment in the last decade. Both NK cells and T cells are key components of host immunity against malignant cells that are being extensively investigated in the field of cancer immunotherapy. While approaches have been developed to improve the antitumor activity of NK and T cells, the tumor microenvironment remains an obstacle to effective NK and T-cell–based therapies. Here, we demonstrated that cancer-conditioned medium suppresses the antitumor activity of NK cells. Ammonia, a by-product of cancer cell metabolism, accumulated in cancer-conditioned medium and in the tumor microenvironment, and impaired the cytotoxicity of NK cells as well as the efficacy of antibody-based and chimeric antigen receptor (CAR) NK and CAR T-cell–based therapies in vitro. Ammonia induced NK and T-cell dysfunction by decreasing the amount of mature perforin in secretory lysosomes, which was dependent on its lysosomotropic features and ability to increase pH in acidic compartments. These findings demonstrate that, in addition to its previously described role in promoting tumor growth as a source of nitrogen for tumor biomass, ammonia promotes tumor immune escape by inhibiting both NK and CAR T-cell cytotoxicity. Significance: Ammonia is elevated in the tumor microenvironment and functions as an immunoinhibitory metabolite in cancer by reducing perforin levels, inhibiting NK and T-cell–mediated immunity and limiting the efficacy of immunotherapies.

Chimeric antigen receptor (CAR)-T cell therapy is undeniably a promising tool in combating various types of hematological malignancies. However, it is not yet optimal and a significant number of patients experience a lack of response or relapse after the treatment. Therapy improvement requires careful analysis of the occurring problems and a deeper understanding of the reasons that stand behind them. In this review, we summarize the recent knowledge about CAR-T products’ clinical performance and discuss diversified approaches taken to improve the major shortcomings of this therapy. Especially, we prioritize the challenges faced by CD19 CAR-T cell-based treatment of B cell-derived malignancies and revise the latest insights about mechanisms mediating therapy resistance. Since the loss of CD19 is one of the major obstacles to the success of CAR-T cell therapy, we present antigens that could be alternatively used for the treatment of various types of B cell-derived cancers.

CD19 CAR-T cells have established a new standard for relapsed/refractory B-cell malignancies. However, the treatment fails in 50% of patients, often due to CD19 antigen loss. Alternative immunotherapies targeting other antigens are being tested but show limited efficacy, especially in cases of lineage switching or loss of B-cell phenotype, highlighting the need for novel targets. Herein, we identified leukocyte-immunoglobulin-like-receptor-B1 (LILRB1, CD85j) as a novel target for CAR-T cells through cell surface proteomics on patient-derived samples of high-risk B-cell acute lymphoblastic leukemia (B-ALL). LILRB1, an immune inhibitory receptor, is normally expressed only on monocytes and B-cells. We observed stable LILRB1 expression in B-ALL and B-cell non-Hodgkin lymphoma (B-NHL), even after CD20/CD19-based immunotherapies. LILRB1 CAR-T cells showed antigen-specific antitumor activity in vitro against B-ALL/B-NHL cells, including those resistant to CD19 CAR-T-cells, and in vivo in B-ALL xenografts. Additionally, we identified LILRB1 in monocytic acute myeloid leukemia (AML) and demonstrated LILRB1 CAR-T cell cytotoxicity against AML cell lines in vitro and in vivo. These findings establish LILRB1 as a novel target for cancer immunotherapy and show evidence for the preclinical efficacy of LILRB1 CAR-T cells against haematological malignancies, including cases resistant to previous lines of immunotherapy, thus holding promise for further clinical development.