The T-win® technology is an innovative investigational approach designed to activate the body’s endogenous anti-regulatory T cells (anti-Tregs) to target regulatory as well as malignant cells. ...Anti-Tregs are naturally occurring T cells that can directly react against regulatory immune cells because they recognize proteins that these targets express, including indoleamine 2,3-dioxygenase (IDO), tryptophan 2,6-dioxygenase, arginase, and programmed death ligand 1 (PD-L1). The T-win® technology is characterized by therapeutic vaccination with long peptide epitopes derived from these antigens and therefore offers a novel way to target genetically stable cells with regular human leukocyte antigen expression in the tumor microenvironment. The T-win® technology thus also represents a novel way to attract pro-inflammatory cells to the tumor microenvironment where they can directly affect immune inhibitory pathways, potentially altering tolerance to tumor antigens. The modification of an immune regulatory environment into a pro-inflammatory milieu potentiates effective anti-tumor T cell responses. Many regulatory immune cells may be reverted into effector cells given the right stimulus. Because T-win® technology is based on the immune-modulatory function of the vaccines, the vaccines activate both CD4 and CD8 anti-Tregs. Of importance, in clinical trials, vaccinations against IDO or PD-L1 to potentiate anti-Tregs have so far proved to be safe, with minimal toxicity.
The gut microbiota is essential for human health and plays an important role in the pathogenesis of several diseases. Short-chain fatty acids (SCFA), such as acetate, butyrate and propionate, are ...end-products of microbial fermentation of macronutrients that distribute systemically via the blood. The aim of this study was to investigate the transcriptional response of immature and LPS-matured human monocyte-derived DC to SCFA. Our data revealed distinct effects exerted by each individual SCFA on gene expression in human monocyte-derived DC, especially in the mature ones. Acetate only exerted negligible effects, while both butyrate and propionate strongly modulated gene expression in both immature and mature human monocyte-derived DC. An Ingenuity pathway analysis based on the differentially expressed genes suggested that propionate and butyrate modulate leukocyte trafficking, as SCFA strongly reduced the release of several pro-inflammatory chemokines including CCL3, CCL4, CCL5, CXCL9, CXCL10, and CXCL11. Additionally, butyrate and propionate inhibited the expression of lipopolysaccharide (LPS)-induced cytokines such as IL-6 and IL-12p40 showing a strong anti-inflammatory effect. This work illustrates that bacterial metabolites far from the site of their production can differentially modulate the inflammatory response and generally provides new insights into host-microbiome interactions.
Short chain fatty acids (SCFAs), such as acetate, butyrate and propionate, are products of microbial macronutrients fermentation that distribute systemically and are believed to modulate host immune ...responses. Recent data have indicated that certain SCFAs, such as butyrate and propionate, directly modulate human dendritic cell (DC) function. Given the role of DCs in initiating and shaping the adaptive immune response, we now explore how SCFAs affect the activation of antigen-specific CD8
T cells stimulated with autologous, MART1 peptide-pulsed DC. We show that butyrate reduces the frequency of peptide-specific CD8
T cells and, together with propionate, inhibit the activity of those cells. On the contrary, acetate does not affect them. Importantly, butyrate and propionate inhibit the production of IL-12 and IL-23 in the DCs and exogenous IL-12 fully restores the activation of the MART-1-specific CD8
T cells, whereas IL-23 has no effect. In conclusion, these results point to a pivotal role of butyrate and propionate in modulating CD8
T cell activation via the inhibition of IL-12 secretion from DCs. These findings reveal a novel mechanism whereby bacterial fermentation products may modulate CD8
T cell function with possible implications in anti-cancer immunotherapy.
Many different therapeutic strategies focus on targeting tumor-associated macrophages (TAMs), due to their vital role in creating an immune suppressive tumor microenvironment (TME) with the aim to ...deplete, repro-gram or target the functional mediators secreted by these cells. Immune modulatory vaccination is an emerging strategy to target immune suppressive myeloid populations in the TME. In contrast to the other clinical strategies that target TAMs, this combines both TAM depletion (through direct killing by cytotoxic T cells) and TAM reprogramming (by introducing pro-inflammatory cytokines into the immune suppressive microenvironment).
The RAS mutations are the most frequently occurring somatic mutations in humans, and several studies have established that T cells from patients with RAS-mutant cancer recognize and kill RAS-mutant ...cells. Enhancing the T cell response via therapeutic cancer vaccination against mutant RAS results in a clinical benefit to patients; thus, T cells specific to RAS mutations are effective at battling cancer. As the theory of cancer immuno-editing indicates that healthy donors may clear malignantly transformed cells via immune-mediated killing, and since T cells have been shown to recognize RAS-mutant cancer cells, we investigated whether healthy donors harbor T-cell responses specific to mutant RAS. We identified strong and frequent responses against several epitopes derived from the RAS codon 12 and codon 13 mutations. Some healthy donors demonstrated a response to several mutant epitopes, and some, but not all, exhibited cross-reactivity to the wild-type RAS epitope. In addition, several T cell responses were identified against mutant RAS epitopes in healthy donors directly ex vivo. Clones against mutant RAS epitopes were established from healthy donors, and several of these clones did not cross-react with the wild-type epitope. Finally, CD45RO+ memory T cells from healthy donors demonstrated a strong response to several mutant RAS epitopes. Taken together, these data suggest that the immune system in healthy donors spontaneously clears malignantly transformed RAS-mutant cells, and the immune system consequently generates T-cell memory against the mutations.
Arginase-1 (Arg1) is expressed by regulatory myeloid cells in the tumor microenvironment (TME), where they play a pro-tumorigenic and T-cell suppressive role. Arg1-specific CD4+ and CD8+ memory T ...cells have been observed in both healthy individuals and cancer patients. However, while the function of anti-regulatory Arg1-specific CD4+ T cells has been characterized, our knowledge of CD8+ Arg1-specific T cells is only scarce. In the current study, we describe the immune-modulatory capabilities of CD8+ Arg1-specific T cells. We generated CD8+ Arg1-specific T cell clones to target Arg1-expressing myeloid cells. Our results demonstrate that these T cells recognize both malignant and nonmalignant regulatory myeloid cells in an Arg1-expression-dependent manner. Notably, Arg1-specific CD8+ T cells possess cytolytic effector capabilities. Immune modulatory vaccines (IMVs) represent a novel treatment modality for cancer. The activation of Arg1-specific CD8+ T cells through Arg1-based IMVs can contribute to the modulatory effects of this treatment strategy.
The identification and characterization of tumor antigens are central objectives in developing anti-cancer immunotherapy. Traditionally, tumor-associated antigens (TAAs) are considered relatively ...restricted to tumor cells (i.e., overexpressed proteins in tumor cells), whereas tumor-specific antigens (TSAs) are considered unique to tumor cells. Recent studies have focused on identifying patient-specific neoantigens, which might be highly immunogenic because they are not expressed in normal tissues. The opposite strategy has emerged with the discovery of anti-regulatory T cells (anti-Tregs) that recognize and attack many cell types in the tumor microenvironment, such as regulatory immune cells, in addition to tumor cells. The term proposed in this review is “tumor microenvironment antigens” (TMAs) to describe the antigens that draw this attack. As therapeutic targets, TMAs offer several advantages that differentiate them from more traditional tumor antigens. Targeting TMAs leads not only to a direct attack on tumor cells but also to modulation of the tumor microenvironment, rendering it immunocompetent and tumor-hostile. Of note, in contrast to TAAs and TSAs, TMAs also are expressed in non-transformed cells with consistent human leukocyte antigen (HLA) expression. Inflammation often induces HLA expression in malignant cells, so that targeting TMAs could additionally affect tumors with no or very low levels of surface HLA expression. This review defines the characteristics, differences, and advantages of TMAs compared with traditional tumor antigens and discusses the use of these antigens in immune modulatory vaccines as an attractive approach to immunotherapy. Different TMAs are expressed by different cells and could be combined in anti-cancer immunotherapies to attack tumor cells directly and modulate local immune cells to create a tumor-hostile microenvironment and inhibit tumor angiogenesis. Immune modulatory vaccines offer an approach for combinatorial therapy with additional immunotherapy including checkpoint blockade, cellular therapy, or traditional cancer vaccines. These combinations would increase the number of patients who can benefit from such therapeutic measures, which all have optimal efficiency in inflamed tumors.
Cytotoxic T Cells Andersen, Mads Hald; Schrama, David; thor Straten, Per ...
Journal of investigative dermatology,
January 2006, 2006-01-00, 2006-Jan, 20060101, Letnik:
126, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The immune system is a complex arrangement of cells and molecules that preserve the integrity of the organism by elimination of all elements judged dangerous. Within the immune system, a humoral and ...a cellular as well as an innate and an adaptive arm can be differentiated. The key players of adaptive cellular immune responses are T lymphocytes in general and, for the effector function, cytotoxic T lymphocytes (CTLs) in particular. T lymphocytes arise in the bone marrow and migrate to the thymus for maturation. During this process, T cells somatically rearrange gene segments, eventually leading to the expression of a unique antigen-binding molecule, the T-cell receptor (TCR). This receptor allows them to monitor all cells of the body, ready to destroy any cell posing a threat to the organism. Cytotoxicity is exerted directly through the Fas or perforin pathway and/or indirectly by the release of cytokines. Obviously, the activity of such a potent cell is tightly regulated. Indeed, a predominance of stimulatory over inhibitory signals is required for effective immune responses to pathogens, and a predominance of inhibitory over stimulatory signals is required for maintenance of self-tolerance. Still, several situations occur in which an inappropriate CTL response leads to either autoimmune disease or persistence of pathogens.
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