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Summary: Murine cytomegalovirus (MCMV) infection of macrophages relies on MCMV-encoded chemokine 2 (MCK2), while infection of fibroblasts occurs independently of MCK2. Recently, MCMV infection of both cell types was found to be dependent on cell-expressed neuropilin 1. Using a CRISPR screen, we now identify that MCK2-dependent infection requires MHC class Ia/β-2-microglobulin (B2m) expression. Further analyses reveal that macrophages expressing MHC class Ia haplotypes H-2b and H-2d, but not H-2k, are susceptible to MCK2-dependent infection with MCMV. The importance of MHC class I expression for MCK2-dependent primary infection and viral dissemination is highlighted by experiments with B2m-deficient mice, which lack surface expression of MHC class I molecules. In those mice, intranasally administered MCK2-proficient MCMV mimics infection patterns of MCK2-deficient MCMV in wild-type mice: it does not infect alveolar macrophages and subsequently fails to disseminate into the salivary glands. Together, these data provide essential knowledge for understanding MCMV-induced pathogenesis, tissue targeting, and virus dissemination.

Immunotherapy has emerged as a promising therapeutic approach for cancer treatment by harnessing the immune system to target cancer cells. However, the efficacy of immunotherapy is hindered by the tumor microenvironment (TME), comprising regulatory T cells (Tregs), macrophages, myeloid-derived suppressor cells (MDSCs), neutrophils, soluble factors (TGF-β, IL-35, IL-10), and hypoxia. These components interact with inhibitory receptors (IRs) on T cells, leading to alterations in T cell transcriptomes, epigenomes, and metabolism, ultimately resulting in T cell exhaustion and compromising the effectiveness of immunotherapy. T cell exhaustion occurs in two phases: pre-exhaustion and exhaustion. Pre-exhausted T cells exhibit reversibility and distinct molecular properties compared to terminally exhausted T cells. Understanding these differences is crucial for designing effective interventions. This comprehensive review summarizes the characteristics of pre-exhausted and exhausted T cells and elucidates the influence of TME components on T cell activity, transcriptomes, epigenomes, and metabolism, ultimately driving T cell exhaustion in cancer. Additionally, potential intervention strategies for reversing exhaustion are discussed. By gaining insights into the mechanisms underlying T cell exhaustion and the impact of the TME, this review aims to inform the development of innovative approaches for combating T cell exhaustion and enhancing the efficacy of immunotherapy in cancer treatment. PLAIN LANGUAGE SUMMARY: The immune system normally attacks any external factor or abnormal cell in the body, however, sometimes abnormal cells such as cancerous cells can escape the immune system and form a tumor. A class of therapy known as immunotherapy relies on reinforcing the immune system in fighting cancerous cells. However, it cannot have a sustained effect because due to chronic exposure to cancerous cells, T cells, which are the pivotal cells in anti-cancer immunity, gradually lose their activity, a phenomenon known as T cell exhaustion. Exhausted T cells differ from normal T cells in metabolism, transcriptomes, and epigenomes and express different molecules, consequently leading to their dysfunction. By having a comprehensive knowledge of exhausted T cells properties and the factors that give rise to exhaustion, scientists can think of new strategies to make immunotherapy more robust. [ABSTRACT FROM AUTHOR]

Background. Gastrosphere, an enriched cellular population with stem-like properties believed to be responsible for an escape from immune-mediated destruction. Th17 and Treg cells play a major role in gastric cancer; however, their interaction with gastrospheres remained elusive. Method. Peripheral blood mononuclear cells were isolated from healthy donors and were cultured with conditioned media of MKN-45 (parental) cells as well as gastrospheres’ conditioned media in the context of mixed lymphocyte reaction and in the presence of anti-CD3/CD28 beads. The proliferation was evaluated using CFSE staining; the percentages of CD4+CD25+FoxP3+ Treg and CD4+IL-17+ Th17 cells and IFN-γ+cells and the production of IL-17, TGF-β, and IL-10 were assessed by flow cytometry and ELISA, respectively. Finally, the cytotoxic potential of induced immune cells was measured by examining the secretion of lactate dehydrogenase from target cells. Results. The results revealed a decreased expansion of PBMCs postexposure to gastrospheres’ conditioned medium which was concomitant with an increased percentage of Th17 and an enhanced Th17 to Treg ratio. The conditioned media of gastrospheres enhanced the secretion of IL-10 and IL-17 and decreased TGF-β. Interestingly, immune cells induced by gastrospheres showed significant cytotoxicity in terms of producing IFN-γ and death induction in target cells. All these changes were related to the upregulation of IL-6, IL-10, and IL-22 in gastrospheres compared to parental cells. Conclusion. Our study showed that the condition media of gastrospheres can potentially induce Th17 with increasing in their cytotoxic effect. Based on our knowledge, the present study is the first study that emphasizes the role of gastrospheres in the induction of antitumor Th17 cells. However, it should be confirmed with complementary studies in vivo.

Gastric cancer stem cells (GCSCs), a small population among tumor cells, are responsible for tumor initiation, development, metastasis, and recurrence. They play a crucial role in immune evasion, immunomodulation, and impairment of effector immunity and believed to be emerged to change the balance of the immune system, importantly CD4+ T cells in the chronic inflamed tumor site. However, different subtypes of innate and adaptive immune cells are involved in the formation of the immune system in the tumor microenvironment, we would look at T cells in this study. Tumor microenvironment induces differentiation of CD4+ T cells into different subsets of T cells, mainly suppressive regulatory T cells (Treg), and T helper 17 (Th17) cells, although their exact role in tumor immunity is still under debate depending on tumor types and stages. Counterbalance between Th17 and Treg cells in the gastrointestinal system result in the homeostasis and normal function of the immune system, particularly mucosal immunity. Recent data demonstrated a high infiltration of Th17 and Treg cells into the gastric tumor site and proved that tumor microenvironment might disturb the balance between Th17 and Treg. It is possible to assume an association between activation of CSCs which contribute to metastasis in late stages, and the imbalanced Th17/Treg cells observed in advanced gastric cancer patients. This review intends to clarify the importance of gastric tumor microenvironment specifically CSCs in relation to Th17/Tregs balance firstly and to highlight the relevance of imbalanced Th17/Treg subsets in determining the stages and behavior of the tumor secondly. Finally, the present study suggests a clinical approach looking at the plasticity of T cells with a focus on Th17 as a promising dedicated arm in cancer immunotherapy.

Background: Gastrosphere, an enriched cellular population with stem-like properties believed to be responsible for an escape from immune-mediated destruction. Th17 and Treg cells play a major role in gastric cancer; however, their interaction with gastrospheres remained elusive.Method: Peripheral blood mononuclear cells were isolated from healthy donors and were cultured with conditioned media of MKN-45 (parental) cells as well as gastrospheres' conditioned media in the context of mixed lymphocyte reaction and in the presence of anti-CD3/CD28 beads. The proliferation was evaluated using CFSE staining; the percentages of CD4+CD25+FoxP3+ Treg and CD4+IL-17+ Th17 cells and IFN-γ+cells and the production of IL-17, TGF-β, and IL-10 were assessed by flow cytometry and ELISA, respectively. Finally, the cytotoxic potential of induced immune cells was measured by examining the secretion of lactate dehydrogenase from target cells.Results: The results revealed a decreased expansion of PBMCs postexposure to gastrospheres' conditioned medium which was concomitant with an increased percentage of Th17 and an enhanced Th17 to Treg ratio. The conditioned media of gastrospheres enhanced the secretion of IL-10 and IL-17 and decreased TGF-β. Interestingly, immune cells induced by gastrospheres showed significant cytotoxicity in terms of producing IFN-γ and death induction in target cells. All these changes were related to the upregulation of IL-6, IL-10, and IL-22 in gastrospheres compared to parental cells.Conclusion: Our study showed that the condition media of gastrospheres can potentially induce Th17 with increasing in their cytotoxic effect. Based on our knowledge, the present study is the first study that emphasizes the role of gastrospheres in the induction of antitumor Th17 cells. However, it should be confirmed with complementary studies in vivo. [ABSTRACT FROM AUTHOR]

Failure of treatment strategies against cancers is a major issue engaging many scientists to investigate the possible resistance factors. Cancer stem cells (CSCs) subvert promising therapeutic methods by developing resistant cancers. These pluripotent cells are located in individual microenvironments called cancer niche. CSCs affect the immune cells and on the flip side, the immune cells in the cancer niche influence them. Thereby, the interaction between CSCs and immune cells in cancer niche needs to be clearly studied in order to develop novel efficient methods of immune-based cancer treatment. In this article, we review literature about the suggested methods of CSC escape from immune responses and the effect of cancer niche characteristics on the ability of CSCs to develop resistant strains of cancers. Moreover, we discuss immune-mediated tumor targeting methods and bring in trials focused on CSC targeted therapies. We aim to help physicians to reach a consensus about using CSC-targeted immunotherapy methods and emerge novel immunotherapy methods through disrupting the interaction between immune cells and CSCs in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Gastric cancer stem cells (GCSCs), a small population among tumor cells, are responsible for tumor initiation, development, metastasis, and recurrence. They play a crucial role in immune evasion, immunomodulation, and impairment of effector immunity and believed to be emerged to change the balance of the immune system, importantly CD4+ T cells in the chronic inflamed tumor site. However, different subtypes of innate and adaptive immune cells are involved in the formation of the immune system in the tumor microenvironment, we would look at T cells in this study. Tumor microenvironment induces differentiation of CD4+ T cells into different subsets of T cells, mainly suppressive regulatory T cells (Treg), and T helper 17 (Th17) cells, although their exact role in tumor immunity is still under debate depending on tumor types and stages. Counterbalance between Th17 and Treg cells in the gastrointestinal system result in the homeostasis and normal function of the immune system, particularly mucosal immunity. Recent data demonstrated a high infiltration of Th17 and Treg cells into the gastric tumor site and proved that tumor microenvironment might disturb the balance between Th17 and Treg. It is possible to assume an association between activation of CSCs which contribute to metastasis in late stages, and the imbalanced Th17/Treg cells observed in advanced gastric cancer patients. This review intends to clarify the importance of gastric tumor microenvironment specifically CSCs in relation to Th17/Tregs balance firstly and to highlight the relevance of imbalanced Th17/Treg subsets in determining the stages and behavior of the tumor secondly. Finally, the present study suggests a clinical approach looking at the plasticity of T cells with a focus on Th17 as a promising dedicated arm in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Adaptive T-cell immunotherapy holds great promise for the successful treatment of leukemia, as well as other types of cancers. More recently, it was also shown to be an effective treatment option for chronic virus infections in immunosuppressed patients. Autologous or allogeneic T cells used for immunotherapy are usually genetically modified to express novel T-cell or chimeric antigen receptors. The production of such cells was significantly simplified with the CRISPR/Cas system, allowing for the deletion or insertion of novel genes at specific locations within the genome. In this review, we describe recent methodological breakthroughs that were important for the conduction of these genetic modifications, summarize crucial points to be considered when conducting such experiments, and highlight the potential pitfalls of these approaches. [ABSTRACT FROM AUTHOR]