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Projeto de investigação
Cancer immunotherapy based on the adoptive transfer of Delta1 T cells
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Publicações
Peripheral clonal selection shapes the human γδ T-cell repertoire
Publication . Di Lorenzo, Biagio; Déchanet-Merville, Julie; Silva-Santos, Bruno
γδ T cells are often placed at the interface between innate and adaptive immunity. These cells share T-cell receptor (TCR) rearrangements and memory functions in common with their αβ T-cell counterparts but differ in terms of their response kinetics and mechanisms of target recognition (Figure 1). Indeed, γδ T cells provide fast responses against infected or transformed cells in a major histocompatibility complex-independent manner, thus participating in the first line of defense, which gives the organism time to mount antigen-specific αβ T-cell responses. Although the four TCR loci were discovered and characterized almost simultaneously, our knowledge of the mechanisms underlying γδ T-cell responses remains insufficient. However, an increasing amount of evidence has demonstrated that γδ T cells recognize self-antigens on the surface of target cells; the expression of these self-antigens is known or expected to increase upon stress, infection or transformation in a TCR-dependent manner, making them an attractive source for cell-based immunotherapies. This response is noted in the case of BTN3A associated with phosphoantigens, lipid-presenting CD1 molecules, endotelial protein C receptor and Annexin A. However, these molecules constitute only a small fraction of the ligands recognized by γδ T cells. In addition, the mechanism by which the γδ TCR repertoire is shaped under physiological conditions and how (much) it changes in response to pathogenic challenge remain poorly understood.
Impact of metabolic resources and infiltrating immune cells on protective responses against solid tumors
Publication . Rodrigues, Neidy Varela; Dias, Sergio Jerónimo Rodrigues; Silva-Santos, Bruno
The tumor microenvironment is composed of different cell types, such as cancer cells, endothelial, fibroblast, stromal cells, and also leukocytes, including γδ T lymphocytes, which participate in anti-tumor immunity. Currently the main strategy for immunotherapy using gamma delta (γδ) T cells is based on the unique reactivity of its dominant subtype in the peripheral blood, Vgamma9Vdelta2 T cells (Vγ9Vδ2 T cells), to antigens of non-peptidic origin (phosphoantigens). Here we investigated the role of systemic cholesterol, namely LDL-cholesterol, in the selective activation and effector functions of T Vγ9Vδ2 cells, particularly in breast cancer. Our results clearly show that LDL-cholesterol was internalized by Vγ9Vδ2 T cells, which was followed by the down-regulation of the LDL receptor (LDL-R), the major cholesterol-carrying lipoprotein receptor. Thereafter, we used human plasma to confirm the effect of the LDL-cholesterol on Vγ9Vδ2 T cell functions. The role of metabolic changes within the immune microenvironment is a timely topic now that there are a variety of cellular therapies utilized to treat cancer patients. In order to understand the role of LDL-cholesterol in the metabolic viability of Vγ9Vδ2 T cells, several parameters were evaluated. In the presence of LDL-cholesterol, the metabolic functions of γδ T cells were significantly inhibited as shown by decreases in mitochondrial mass, mitochondrial DNA, Adenosine triphosphate (ATP) and reactive oxygen species (ROS).
Upon elucidation of the decreased metabolic viability involved in the negative regulation of Vγ9Vδ2 T cell activation by LDL-cholesterol, we next dissected the mechanisms involved in the recognition and interaction with tumor cells. Among the potential cytotoxic receptors, we demonstrated that the expression of Natural Killer group 2D (NKG2D) and DNAX Accessory Molecule-1 (DNAM-1), involved in the recognition of tumor cell ligands, and the potent anti-tumor cytokine interferon gamma (IFN-g), were all impaired in the presence of LDL-cholesterol, thereby affecting the cytotoxic capacity of the Vγ9Vδ2 T cells against breast cancer cells in vitro. Consequently, we conducted in vivo studies to support these findings in a tumor context. As a first approach, we evaluated the anti-tumor capacity of Vγ9Vδ2 T cells previously incubated in the presence or absence of LDL-cholesterol in immunodeficient mice bearing human breast tumors. On the other hand, since obesity is characterized by overproduction of inflammatory cytokines, such as TNF alpha and interleukin-1, which may lead to macrophage activation, we used a second approach to evaluate the impact of a cholesterol-rich microenvironment on the antitumor functions of murine γδ lymphocytes in a syngeneic breast cancer model. In both experiments, the negative impact of LDL-cholesterol on the antitumor functions of γδ T lymphocytes was confirmed, leading to increased tumor growth.
The influence of cholesterol on tumor growth had been demonstrated in previous studies, where mice on a fat diet developed larger tumors compared to mice exposed to "normal" diets. One of the possible explanations offered by our study is that "bad" cholesterol, when at high levels, has an inhibitory effect on γδ T cells that are normally mobilized to destroy tumor cells. Moreover, our work is the first to describe how human Vγ9Vδ2 T cells may be suppressed by high LDL-cholesterol. This new finding can help in the development of immunotherapy against breast cancer, namely towards preserving the lymphocyte activation and functions required to eliminate tumor cells
Working in “NK mode”: natural killer group 2 member D and natural cytotoxicity receptors in stress-surveillance by γδ T cells
Publication . Silva-Santos, Bruno; Strid, Jessica
Natural killer cell receptors (NKRs) are germline-encoded transmembrane proteins that regulate the activation and homeostasis of NK cells as well as other lymphocytes. For γδ T cells, NKRs play critical roles in discriminating stressed (transformed or infected) cells from their healthy counterparts, as proposed in the "lymphoid stress-surveillance" theory. Whereas the main physiologic role is seemingly fulfilled by natural killer group 2 member D, constitutively expressed by γδ T cells, enhancement of their therapeutic potential may rely on natural cytotoxicity receptors (NCRs), like NKp30 or NKp44, that can be induced selectively on human Vδ1+ T cells. Here, we review the contributions of NCRs, NKG2D, and their multiple ligands, to γδ T cell biology in mouse and human.
Molecular determinants of target cell recognition by human γδ T Cells
Publication . Simões, André; Di Lorenzo, Biagio; Silva-Santos, Bruno
The unique capabilities of gamma-delta (γδ) T cells to recognize cells under stressed conditions, particularly infected or transformed cells, and killing them or regulating the immune response against them, paved the way to the development of promising therapeutic strategies for cancer and infectious diseases. From a mechanistic standpoint, numerous studies have unveiled a remarkable flexibility of γδ T cells in employing their T cell receptor and/or NK cell receptors for target cell recognition, even if the relevant ligands often remain uncertain. Here, we review the accumulated knowledge on the diverse mechanisms of target cell recognition by γδ T cells, focusing on human γδ T cells, to provide an integrated perspective of their therapeutic potential in cancer and infectious diseases.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
3599-PPCDT
Número da atribuição
PTDC/DTP-PIC/4931/2014