T cells recognize neoepitope peptide-major histocompatibility complex class I on cancer cells. The strength (or avidity) of the cell receptor–peptide-major interaction is a critical variable in immune control cancers. Here, we analyze neoepitope-specific CD8 distinct avidities and show that low-avidity are sole mediators mice solely responsive to checkpoint blockade humans. High-avidity ineffective immune-suppressive. mechanistic basis these differences lies higher exhaustion status...

Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through receptors. Here, we uncover a role for AEA its receptor, receptor 2 (CB2), in regulation immune tolerance gut pancreas. This work demonstrates major immunological endocannabinoid. The pungent molecule capsaicin (CP) has similar...

Abstract Cytotoxic CD4 Th1 cells are emerging as a therapeutically useful T cell lineage that can effectively target tumors, but until now the pathways govern their differentiation have been poorly understood. We demonstrate CD134 (OX40) costimulation programs naive self- and virus-reactive to undergo in vivo into cytotoxic effectors. CD137 (4-1BB) maximized clonal expansion, IL-2 was necessary for differentiation. Importantly, T-box transcription factor Eomesodermin critical inducing marker...

Heat-shock proteins (HSPs), or stress proteins, are abundant and highly conserved, present in all organisms cells. Selected HSPs, also known as chaperones, play crucial roles folding unfolding of assembly multiprotein complexes, transport sorting into correct subcellular compartments, cell-cycle control signaling, protection cells against apoptosis. More recently, HSPs have been shown to be key players immune responses: during antigen presentation well cross-priming, they chaperone transfer...

Abstract The ability of mature T lymphocytes to develop effector capacity after encounter with cognate Ag is generally dependent upon inflammatory signals associated infection that induce dendritic cell activation/maturation. These can derive directly from pathogens or be expressed by host cells in response infection. Heat shock proteins (HSPs) are a class host-derived mediators perform the duel function both chaperoning MHC I-restricted epitopes into cross-presentation pathway DCs and...

Abstract Insertion or deletion of one two base pairs within a coding region causes frameshift, which has the potential to generate neoepitopes (InDel-generated neoepitopes) that lack self-counterpart and are entirely novel. Despite obvious appeal InDel-generated neoepitopes, demonstration such candidate can elicit CD8 T-cell response, no actually control tumors in vivo have been reported thus far. Here, mouse colon carcinoma line, we identify 11 InDels, only generates neoepitope elicits...

Identification of neoepitopes that are effective in cancer therapy is a major challenge creating vaccines. Here, using an entirely unbiased approach, we queried all possible mouse model and asked which those mediating tumor rejection and, independently, eliciting measurable CD8 response. This analysis uncovered large trove anticancer have strikingly different properties from conventional epitopes suggested algorithm to predict them. It also revealed our current methods prediction discard the...

High-affinity MHC I-peptide interactions are considered essential for immunogenicity. However, some neo-epitopes with low affinity I have been reported to elicit CD8 T cell dependent tumor rejection in immunization-challenge studies. Here we show a mouse model that neo-epitope poorly binds is able enhance the immunogenicity of absence immunization. Fibrosarcoma cells naturally occurring mutation edited their wild type counterpart; then re-introduced order obtain line genetically identical...

Summary Tick feeding modulates host immune responses. Tick‐induced skewing of CD4 + T cells towards a Th2 cytokine profile facilitates transmission tick‐borne pathogens that would otherwise be neutralized by Th1 cytokines. Tick‐derived factors drive this response have not previously been characterized. In the current study, we examined an I. scapularis cDNA library prepared at 18–24 h and identified expressed tick gene with homology to Loxosceles spider venom proteins sphingomyelinase...

T‐cell tolerance to tumor antigens represents a major hurdle in generating immunity. Combined administration of agonistic monoclonal antibodies (mAbs) the costimulatory receptors CD134 plus CD137 can program T‐cells responding tolerogenic antigen undergo expansion, and effector differentiation, also elicits Nevertheless, agonists engage inhibitory immune components. To understand how stimulatory versus components are regulated during dual costimulation (DCo), current study utilized model...

Abstract BACKGROUND Prostate cancer promotes the development of T cell tolerance towards prostatic antigens, potentially limiting efficacy prostate vaccines targeting these antigens. Here, we sought to determine stage disease progression when develops, as well role steady state dendritic cells (DC) and CD4 + CD25 regulatory (Tregs) in programming tolerance. METHODS The response naïve HA‐specific were analyzed following adoptive transfer into Pro‐HA × TRAMP transgenic mice harboring...

Abstract Bone marrow-derived APC are critical for both priming effector/memory T cell responses to pathogens and inducing peripheral tolerance in self-reactive cells. In particular, dendritic cells (DC) can acquire self-Ags under steady state conditions thought present them cognate a default tolerogenic manner, whereas exposure pathogen-associated inflammatory mediators during the acquisition of pathogen-derived Ags appears reprogram DCs prime effector memory function. Recent studies have...

Abstract We compared how CD4 vs CD8 cells attain the capacity to express effector cytokine IFN-γ under both immunogenic and tolerogenic conditions. Although Ifng gene locus was epigenetically repressed in naive Ag-inexperienced cells, it had already undergone partial remodeling toward a transcriptionally competent configuration cells. After TCR stimulation, fully remodeled gained high levels of more rapidly than Enforced dual costimulation through OX40 4-1BB redirected encountering soluble...

Abstract Agonists to the TNF/TNFR costimulatory receptors CD134 (OX40) and CD137 (4-1BB) elicit antitumor immunity. Dual costimulation with anti-CD134 plus anti-CD137 is particularly potent because it programs cytotoxic potential in CD8+ CD4+ T cells. Cytotoxicity dual-costimulated CD4 cells depends on T-box transcription factor eomesodermin (Eomes), which we report induced via a mechanism that does not rely IL-2, contrast CTL, but rather CD8 cell lineage commitment Runx3, supports Eomes...

Abstract When Th1 effector CD4 cells encounter tolerizing Ag in vivo, their capacity to express the cytokines IFN-γ and TNF-α is lost more rapidly than noneffector functions such as IL-2 production proliferation. To localize relevant intracellular signaling defects, cytokine expression was compared following restimulation with vs agents that bypass TCR-proximal signaling. were both partially rescued when bypassed, indicating -distal defects impair of these two cytokines. In contrast,...

Abstract Cbl-b is an E3 ubiquitin ligase that limits Ag responsiveness in T cells by targeting TCR-inducible signaling molecules. deficiency thus renders hyperresponsive to antigenic stimulation and predisposes individuals toward developing autoimmunity. In part because Cbl-b−/− do not require CD28 costimulation become activated, insufficient a critical parameter confers anergy induction over effector differentiation, it has been hypothesized are resistant anergy. This possibility supported...

Abstract When naive CD4+ Th cells encounter cognate pathogen-derived Ags they expand and develop the capacity to express appropriate effector cytokines for neutralizing pathogen. Central this differentiation process are epigenetic modifications within cytokine genes that allow accessibility transcriptional machinery. In contrast, when mature self-reactive CD4 their epitopes in periphery generally undergo a of tolerization which become hyporesponsive/anergic antigenic stimulation. current...

High-throughput DNA and RNA sequencing are revolutionizing precision oncology, enabling personalized therapies such as cancer vaccines designed to target tumor-specific neoepitopes generated by somatic mutations expressed in cells. Identification of these from next-generation data clinical samples remains challenging requires the use complex bioinformatics pipelines. In this paper, we present GeNeo, a toolbox for genomics-guided neoepitope prediction. GeNeo includes comprehensive set tools...

Abstract CD8 T cells which recognize neoepitopes are central to immune control of cancers. cells, through cell receptors, neoepitope peptide-MHC I on cancer cells. The strength (or avidity) the receptor- peptide-MHCI interaction is a critical variable in cancers vivo. Here, analyzing neoepitope-specific distinct avidities validated mouse tumor, low avidity observed be sole mediators Low also solely responsive checkpoint blockade mice and humans. High not only ineffective but suppress...

Abstract The intricate interplay between the nervous and immune systems significantly influences fate of cells in homeostasis as well under pathological conditions such cancer. Notably, adrenergic signals from sympathetic system have been identified regulators hematopoiesis. Disruption signaling has linked to mal-differentiation myeloid lymphoid lineages leading emergence Tregs, myeloid-derived suppressor cells, exhaustion CD8+ T cells. We show here that disrupted also leads erythroid...

Abstract The interaction of T cell receptors (TCRs) on cells with MHC I-peptide complexes cancer elicits the cytotoxic activity CD8 +T cells. Here we analyze how strength this interaction, or avidity, shapes exhaustion +TILs and dictates anti-tumor immunity. We developed a novel tetramer decay assay to isolate based their TCR avidities. used method study low high avidity responding tumor neoantigen PDPR MUTof murine sarcoma Meth A. Single sequencing reveals that are more terminally exhausted...

Abstract The frequency of CD8+ tumor infiltrating lymphocytes (TILs) has been positively associated with overall survival in several cancers. interaction T cell receptors (TCRs) on cells Major Histocompatibility Complex (MHC)-peptide complexes cancer elicits the cytotoxic activity cells. Here we set out to understand how strength this interaction, or avidity, shapes phenotype TILs and that dictates anti-tumor immunity. We developed a novel tetramer decay assay isolate based their TCR...

Abstract Neoepitopes presented in the context of MHC render tumors immunogenic. However, not all potential neoepitopes elicit immunity, and attributes immunogenic are yet to be fully defined. Based on premise that regressing must T cells recognize true anti-tumor neoepitopes, we have developed used here an ELISPOT based high-throughput assay allows testing immunogenicity a large number candidate neoepitopes. Naïve C57BL/6 mice were challenged with colorectal tumor line MC38 treated, starting...

Abstract Somatic mutations in cancer cells can give rise to new MHC epitopes referred as neoepitopes. Neoepitopes have been clearly demonstrated elicit an antigen specific T cell response, which are capable of mediating targeted killing cells. Despite recent advancements, exactly what criteria make a good neoepitope for personalized therapy is currently unknown. Here, using syngeneic tumor C57BL/6 mice, named FABF, we present results exhaustive and exhausting study where tested hundreds long...