The Pathophysiological Relevance of the iNKT Cell/Mononuclear Phagocyte Crosstalk in Tissues

CD1d-restricted Natural Killer T (NKT) cells are regarded as sentinels of tissue integrity by sensing local cell stress and damage. This occurs via recognition of CD1d-restricted lipid antigens, generated by stress-related metabolic changes, and stimulation by inflammatory cytokines, such as IL-12 and IL-18. Increasing evidence suggest that this occurs mainly upon NKT cell interaction with CD1d-expressing cells of the Mononuclear Phagocytic System, i.e., monocytes, macrophages and DCs, which patrol parenchymatous organs and mucosae to maintain tissue homeostasis and immune surveillance. In this review, we discuss critical examples of this crosstalk, presenting the known underlying mechanisms and their effects on both cell types and the environment, and suggest that the interaction with CD1d-expressing mononuclear phagocytes in tissues is the fundamental job of NKT cells

Invariant NKT cells contribute to chronic lymphocytic leukemia surveillance and prognosis

Chronic lymphocytic leukemia (CLL) is characterized by the expansion of malignant CD5(+) B lymphocytes in blood, bone marrow and lymphoid organs. CD1d-restricted invariant Natural Killer T (iNKT) cells are innate-like T lymphocytes strongly implicated in tumor surveillance. We investigated the impact of iNKT cells in the natural history of the disease both in Eμ;-Tcl1 (Tcl1) CLL mouse model and 68 CLL patients. We found that Tcl1-CLL cells express CD1d and iNKT cells critically delay the disease onset, but become functionally impaired upon disease progression. In patients, disease progression correlates also with high CD1d expression on CLL cells and impaired iNKT cells. Conversely, disease stability correlates with negative/low CD1d expression on CLL cells and normal iNKT cells, suggesting an indirect leukemia control. iNKT cells indeed hinder CLL survival in vitro by restraining CD1d-expressing Nurse Like Cells, a relevant pro-leukemia macrophage population. Finally, multivariate analysis identifies iNKT cell frequency as independent predictor of disease progression. Together, these results support iNKT cell contribution to CLL immune-surveillance and highlight iNKT cell frequency as prognostic marker for disease progression

Bimodal CD40/Fas-Dependent Crosstalk between iNKT Cells and Tumor-Associated Macrophages Impairs Prostate Cancer Progression

Heterotypic cellular and molecular interactions in the tumor microenvironment (TME) control cancer progression. Here, we show that CD1d-restricted invariant natural killer (iNKT) cells control prostate cancer (PCa) progression by sculpting the TME. In a mouse PCa model, iNKT cells restrained the proangiogenic and immunosuppressive capabilities of tumor-infiltrating immune cells by reducing proangiogenic TIE2+, M2-like macrophages (TEMs), and sustaining pro-inflammatory M1-like macrophages. iNKT cells directly contacted macrophages in the PCa stroma, and iNKT cell transfer into tumorbearing mice abated TEMs, delaying tumor progression. iNKT cells modulated macrophages through the cooperative engagement of CD1d, Fas, and CD40, which promoted selective killing of M2-like and survival of M1-like macrophages. Human PCa aggressiveness associate with reduced intra-tumoral iNKT cells, increased TEMs, and expression of pro-angiogenic genes, underscoring the clinical significance of this crosstalk. Therefore, iNKT cells may control PCa through mechanisms involving differential macrophage modulation, which may be harnessed for therapeutically reprogramming the TME

Fasting renders immunotherapy effective against low-immunogenic breast cancer while reducing side effects

Immunotherapy is improving the prognosis and survival of cancer patients, but despite encouraging out-comes in different cancers, the majority of tumors are resistant to it, and the immunotherapy combinations are often accompanied by severe side effects. Here, we show that a periodic fasting-mimicking diet (FMD) can act on the tumor microenvironment and increase the efficacy of immunotherapy (anti-PD-L1 and anti-OX40) against the poorly immunogenic triple-negative breast tumors (TNBCs) by expanding early exhausted effector T cells, switching the cancer metabolism from glycolytic to respiratory, and reducing collagen depo-sition. Furthermore, FMD reduces the occurrence of immune-related adverse events (irAEs) by preventing the hyperactivation of the immune response. These results indicate that FMD cycles have the potential to enhance the efficacy of anti-cancer immune responses, expand the portion of tumors sensitive to immuno-therapy, and reduce its side effects

Thymic epithelial cell alterations and defective thymopoiesis lead to central and peripheral tolerance perturbation in MHCII deficiency

Major Histocompatibility Complex (MHC) class II (MHCII) deficiency (MHCII-D), also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. Abnormal cross-talk with developing T cells due to the absence of MHCII expression likely leads to defects in thymic epithelial cells (TEC). However, the contribution of TEC alterations to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC in this disease. We observed an overall perturbation of thymic structure and function in both MHCII-/- mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII-/- mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency