Smoothing T cell roads to the tumor: Chemokine post-translational regulation

We described a novel tumor-associated immunosuppressive mechanism based on post-translational modifications of chemokines by reactive nitrogen species (RNS). To overcome tumor immunosuppressive hindrances, we designed and developed a new drug, AT38, that inhibits RNS generation at the tumor site. Combinatorial approaches with AT38 boost the effectiveness of cancer immunotherapy protocols

Tuning cancer fate: the unremitting role of host immunity

Host immunity plays a central and complex role in dictating tumour progression. Solid tumours are commonly infiltrated by a large number of immune cells that dynamically interact with the surrounding microenvironment. At first, innate and adaptive immune cells successfully cooperate to eradicate microcolonies of transformed cells. Concomitantly, surviving tumour clones start to proliferate and harness immune responses by specifically hijacking anti-tumour effector mechanisms and fostering the accumulation of immunosuppressive immune cell subsets at the tumour site. This pliable interplay between immune and malignant cells is a relentless process that has been concisely organized in three different phases: elimination, equilibrium and escape. In this review, we aim to depict the distinct immune cell subsets and immune-mediated responses characterizing the tumour landscape throughout the three interconnected phases. Importantly, the identification of key immune players and molecules involved in the dynamic crosstalk between tumour and immune system has been crucial for the introduction of reliable prognostic factors and effective therapeutic protocols against cancers

T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We\ua0found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8(+) cytotoxic T\ua0cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1(+) myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies

Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells

Tumor-promoted constraints negatively affect cytotoxic T lymphocyte (CTL) trafficking to the tumor core and, as a result, inhibit tumor killing. The production of reactive nitrogen species (RNS) within the tumor microenvironment has been reported in mouse and human cancers. We describe a novel RNS-dependent posttranslational modification of chemokines that has a profound impact on leukocyte recruitment to mouse and human tumors. Intratumoral RNS production induces CCL2 chemokine nitration and hinders T cell infiltration, resulting in the trapping of tumor-specific T cells in the stroma that surrounds cancer cells. Preconditioning of the tumor microenvironment with novel drugs that inhibit CCL2 modification facilitates CTL invasion of the tumor, suggesting that these drugs may be effective in cancer immunotherapy. Our results unveil an unexpected mechanism of tumor evasion and introduce new avenues for cancer immunotherapy

MDSCs and T cells in solid tumors and non-Hodgkin lymphomas: an immunosuppressive speech

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous subset of cells expanded during multiple pathological settings, including cancers. In tumors, MDSCs are dominant drivers of T-cell immunosuppression. To accomplish their job, they exploit multiple mechanisms ultimately leading to the paralysis of anti-tumor immunity. Among the variety of MDSC-ways of working within the tumor microenvironment, the generation of reactive species and the metabolic reprogramming have emerged as pivotal determinants of their immunosuppressive power. In this review we will overview integral mechanisms of MDSC-mediated immunosuppression in solid tumors, with a particular focus on Non-Hodgkin lymphoma.Myeloid-derived suppressor cells (MDSCs) are a heterogeneous subset of cells orchestrating T cell immunosuppression in tumors. To accomplish their job, MDSCs exploit multiple mechanisms of action, including the metabolic reprogramming of T cells and the generation of reactive species. This review focuses on key mechanisms of MDSC-mediated immunosuppression in solid tumors, in particular in Non-Hodgkin lymphoma

Membrane Rafts in T Cell Activation: A Spotlight on CD28 Costimulation

Spatiotemporal compartmentalization of signaling pathways and second messengers is pivotal for cell biology and membrane rafts are, therefore, required for several lymphocyte functions. On the other hand, T cells have the specific necessity of tuning signaling amplification depending on the context in which the antigen is presented. In this review, we discuss of membrane rafts in the context of T cell signaling, focusing on CD28-mediated costimulation

CD28 and chemokine receptors: Signalling amplifiers at the immunological synapse

T cells are master regulators of the immune response tuning, among others, B cells, macrophages and NK cells. To exert their functions requiring high sensibility and specificity, T cells need to integrate different stimuli from the surrounding microenvironment. A finely tuned signalling compartmentalization orchestrated in dynamic platforms is an essential requirement for the proper and efficient response of these cells to distinct triggers. During years, several studies have depicted the pivotal role of the cytoskeleton and lipid microdomains in controlling signalling compartmentalization during T cell activation and functions. Here, we discuss mechanisms responsible for signalling amplification and compartmentalization in T cell activation, focusing on the role of CD28, chemokine receptors and the actin cytoskeleton. We also take into account the detrimental effect of mutations carried by distinct signalling proteins giving rise to syndromes characterized by defects in T cell functionality