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Nature Reviews. Immunology Mar 2024MHC antigen presentation plays a fundamental role in adaptive and semi-invariant T cell immunity. Distinct MHC molecules bind antigens that differ in chemical structure,... (Review)
Review
MHC antigen presentation plays a fundamental role in adaptive and semi-invariant T cell immunity. Distinct MHC molecules bind antigens that differ in chemical structure, origin and location and present them to specialized T cells. MHC class I-related protein 1 (MR1) presents a range of small molecule antigens to MR1-restricted T (MR1T) lymphocytes. The best studied MR1 ligands are derived from microbial metabolism and are recognized by a major class of MR1T cells known as mucosal-associated invariant T (MAIT) cells. Here, we describe the MR1 antigen presentation pathway: the known types of antigens presented by MR1, the location where MR1-antigen complexes form, the route followed by the complexes to the cell surface, the mechanisms involved in termination of MR1 antigen presentation and the accessory cellular proteins that comprise the MR1 antigen presentation machinery. The current road map of the MR1 antigen presentation pathway reveals potential strategies for therapeutic manipulation of MR1T cell function and provides a foundation for further studies that will lead to a deeper understanding of MR1-mediated immunity.
Topics: Humans; Antigen Presentation; Mucosal-Associated Invariant T Cells; Minor Histocompatibility Antigens; Histocompatibility Antigens Class I; Antigens
PubMed: 37773272
DOI: 10.1038/s41577-023-00934-1 -
The Journal of Experimental Medicine Apr 2020Experimental and clinical evidence suggests that tumor-associated macrophages (TAMs) play important roles in cancer progression. Here, we have characterized the ontogeny...
Experimental and clinical evidence suggests that tumor-associated macrophages (TAMs) play important roles in cancer progression. Here, we have characterized the ontogeny and function of TAM subsets in a mouse model of metastatic ovarian cancer that is representative for visceral peritoneal metastasis. We show that the omentum is a critical premetastatic niche for development of invasive disease in this model and define a unique subset of CD163+ Tim4+ resident omental macrophages responsible for metastatic spread of ovarian cancer cells. Transcriptomic analysis showed that resident CD163+ Tim4+ omental macrophages were phenotypically distinct and maintained their resident identity during tumor growth. Selective depletion of CD163+ Tim4+ macrophages in omentum using genetic and pharmacological tools prevented tumor progression and metastatic spread of disease. These studies describe a specific role for tissue-resident macrophages in the invasive progression of metastatic ovarian cancer. The molecular pathways of cross-talk between tissue-resident macrophages and disseminated cancer cells may represent new targets to prevent metastasis and disease recurrence.
Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Disease Models, Animal; Disease Progression; Female; Gene Expression Profiling; Macrophages; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Omentum; Ovarian Neoplasms; Peritoneal Neoplasms; Phenotype; Receptors, Cell Surface; Transcriptome
PubMed: 31951251
DOI: 10.1084/jem.20191869 -
Nature Immunology Sep 2022CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both...
CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both receptors share the same ligands, CD80 and CD86, the specific requirement for two distinct ligands remains obscure. In the present study, we demonstrate that, although CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, this process results in separate fates for CTLA-4 itself. In the presence of CD80, CTLA-4 remained ligand bound, and was ubiquitylated and trafficked via late endosomes and lysosomes. In contrast, in the presence of CD86, CTLA-4 detached in a pH-dependent manner and recycled back to the cell surface to permit further transendocytosis. Furthermore, we identified clinically relevant mutations that cause autoimmune disease, which selectively disrupted CD86 transendocytosis, by affecting either CTLA-4 recycling or CD86 binding. These observations provide a rationale for two distinct ligands and show that defects in CTLA-4-mediated transendocytosis of CD86 are associated with autoimmunity.
Topics: Antigens, CD; Antigens, Differentiation; B7-1 Antigen; B7-2 Antigen; CD28 Antigens; CTLA-4 Antigen; Cell Adhesion Molecules; Ligands; Lymphocyte Activation
PubMed: 35999394
DOI: 10.1038/s41590-022-01289-w -
Molecular Therapy : the Journal of the... Sep 2023Lyme disease is the most common vector-borne infectious disease in the United States, in part because a vaccine against it is not currently available for humans. We...
Lyme disease is the most common vector-borne infectious disease in the United States, in part because a vaccine against it is not currently available for humans. We propose utilizing the lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) platform to generate a Lyme disease vaccine like the successful clinical vaccines against SARS-CoV-2. Of the antigens expressed by Borrelia burgdorferi, the causative agent of Lyme disease, outer surface protein A (OspA) is the most promising candidate for vaccine development. We have designed and synthesized an OspA-encoding mRNA-LNP vaccine and compared its immunogenicity and protective efficacy to an alum-adjuvanted OspA protein subunit vaccine. OspA mRNA-LNP induced superior humoral and cell-mediated immune responses in mice after a single immunization. These potent immune responses resulted in protection against bacterial infection. Our study demonstrates that highly efficient mRNA vaccines can be developed against bacterial targets.
Topics: Humans; Animals; Mice; COVID-19 Vaccines; COVID-19; SARS-CoV-2; Lyme Disease; Antigens, Surface; Bacterial Outer Membrane Proteins
PubMed: 37533256
DOI: 10.1016/j.ymthe.2023.07.022 -
Journal For Immunotherapy of Cancer Jun 2022The immune suppressive tumor microenvironment (TME) that inhibits T cell infiltration, survival, and antitumor activity has posed a major challenge for developing...
BACKGROUND
The immune suppressive tumor microenvironment (TME) that inhibits T cell infiltration, survival, and antitumor activity has posed a major challenge for developing effective immunotherapies for solid tumors. Chimeric antigen receptor (CAR)-engineered T cell therapy has shown unprecedented clinical response in treating patients with hematological malignancies, and intense investigation is underway to achieve similar responses with solid tumors. Immunologically cold tumors, including prostate cancers, are often infiltrated with abundant tumor-associated macrophages (TAMs), and infiltration of CD163 M2 macrophages correlates with tumor progression and poor responses to immunotherapy. However, the impact of TAMs on CAR T cell activity alone and in combination with TME immunomodulators is unclear.
METHODS
To model this in vitro, we utilized a novel co-culture system with tumor cells, CAR T cells, and polarized M1 or M2 macrophages from CD14 peripheral blood mononuclear cells collected from healthy human donors. Tumor cell killing, T cell activation and proliferation, and macrophage phenotypes were evaluated by flow cytometry, cytokine production, RNA sequencing, and functional blockade of signaling pathways using antibodies and small molecule inhibitors. We also evaluated the TME in humanized mice following CAR T cell therapy for validation of our in vitro findings.
RESULTS
We observed inhibition of CAR T cell activity with the presence of M2 macrophages, but not M1 macrophages, coinciding with a robust induction of programmed death ligand-1 (PD-L1) in M2 macrophages. We observed similar PD-L1 expression in TAMs following CAR T cell therapy in the TME of humanized mice. PD-L1, but not programmed cell death protein-1, blockade in combination with CAR T cell therapy altered phenotypes to more M1-like subsets and led to loss of CD163 M2 macrophages via interferon-γ signaling, resulting in improved antitumor activity of CAR T cells.
CONCLUSION
This study reveals an alternative mechanism by which the combination of CAR T cells and immune checkpoint blockade modulates the immune landscape of solid tumors to enhance therapeutic efficacy of CAR T cells.
Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; B7-H1 Antigen; Humans; Immunotherapy; Interferon-gamma; Leukocytes, Mononuclear; Macrophages; Mice; Neoplasms; Receptors, Cell Surface; T-Lymphocytes; Tumor Microenvironment
PubMed: 35738799
DOI: 10.1136/jitc-2021-004400 -
European Journal of Nuclear Medicine... May 2021Various radiolabeled prostate-specific membrane antigen (PSMA)-targeting tracers are clinically applied for prostate cancer (PCa) imaging and targeted radionuclide...
PURPOSE
Various radiolabeled prostate-specific membrane antigen (PSMA)-targeting tracers are clinically applied for prostate cancer (PCa) imaging and targeted radionuclide therapy. The PSMA binding affinities, biodistribution, and DNA-damaging capacities of these radiotracers have not yet been compared in detail. A major concern of PSMA-targeting radiotracers is the toxicity in other PSMA-expressing organs, such as the salivary glands, thus demanding careful evaluation of the most optimal and safest radiotracer. In this extensive preclinical study, we evaluated the clinically applied PSMA-targeting small molecule inhibitors DOTA-PSMA-617 (PSMA-617) and DOTAGA-PSMA-I&T (PSMA-I&T) and the PSMA nanobody DOTA-JVZ-007 (JVZ-007) using PSMA-expressing cell lines, a unique set of PCa patient-derived xenografts (PDX) and healthy human tissues.
METHODS AND RESULTS
In vitro displacement studies on PSMA-expressing cells and cryosections of a PSMA-positive PDX revealed high and specific binding affinity for all three tracers labeled with lutetium-177 with IC values in the nanomolar range. Interestingly, [Lu]Lu-JVZ-007 could not be displaced by PSMA-617 or PSMA-I&T, suggesting that this tracer targets an alternative binding site. Autoradiography assays on cryosections of human salivary and renal tissues revealed [Lu]Lu-PSMA-617 to have the lowest binding to these healthy organs compared with [Lu]Lu-PSMA-I&T. In vivo biodistribution assays confirmed the in vitro results with comparable tumor uptake of [Lu]Lu-PSMA-617 and [Lu]Lu-PSMA-I&T at all timepoints, resulting in induction of similar levels of DNA double-strand breaks in the tumors. However, [Lu]Lu-PSMA-I&T demonstrated approximately 40× higher renal uptake at 4 and 8 h post injection resulting in an unfavorable tumor-to-kidney ratio.
CONCLUSION
[Lu]Lu-PSMA-617 has the most favorable biodistribution in mice as well as more favorable binding characteristics in vitro in PSMA-positive cells and human kidney and salivary gland specimens compared with [Lu]Lu-PSMA-I&T and [Lu]Lu-JVZ-007. Based on our preclinical evaluation, [Lu]Lu-PSMA-617 is the best performing tracer to be taken further into clinical evaluation for PSMA-targeted radiotherapeutic development although with careful evaluation of the tracer binding to PSMA-expressing organs.
Topics: Animals; Antigens, Surface; Cell Line, Tumor; Glutamate Carboxypeptidase II; Humans; Lutetium; Male; Mice; Prostatic Neoplasms; Radioisotopes; Tissue Distribution
PubMed: 33094433
DOI: 10.1007/s00259-020-05057-6 -
Cancer Treatment Reviews Feb 2024Antibody-drug conjugates (ADCs) represent a novel class of molecules composed of a recombinant monoclonal antibody targeted to a specific cell surface antigen,... (Review)
Review
Antibody-drug conjugates (ADCs) represent a novel class of molecules composed of a recombinant monoclonal antibody targeted to a specific cell surface antigen, conjugated to a cytotoxic agent through a cleavable or non-cleavable synthetic linker. The rationale behind the development of ADCs is to overcome the limitations of conventional chemotherapy, such as the narrow therapeutic window and the emergence of resistance mechanisms. ADCs had already revolutionized the treatment algorithm of HER2-positive breast cancer. Currently, emergent non-HER2 targeted ADCs are gaining momentum, with special focus on triple-negative disease therapeutic landscape. Sacituzumab govitecan (SG) is an ADC consisting of a humanized monoclonal antibody hRS7 targeting trophoblast cell surface antigen 2 (Trop2), linked to the topoisomerase I inhibitor SN-38 by a hydrolysable linker. It currently stands as the only non-HER2 targeted ADC that already received approval for the treatment of unresectable locally advanced or metastatic triple negative breast cancer (TNBC) in patients who had received two or more prior systemic therapies, with at least one for advanced disease. The purpose of these review is to analyze the available evidence regarding ADCs in TNBC, alongside with providing an overview on the ongoing and future research horizons in this field.
Topics: Humans; Female; Triple Negative Breast Neoplasms; Breast Neoplasms; Irinotecan; Camptothecin; Immunoconjugates; Antibodies, Monoclonal; Antigens, Surface
PubMed: 38118302
DOI: 10.1016/j.ctrv.2023.102672 -
Oncoimmunology 2022Chimeric antigen receptor (CAR) T cell therapies have resulted in profound clinical responses in the treatment of CD19-positive hematological malignancies, but a...
Chimeric antigen receptor (CAR) T cell therapies have resulted in profound clinical responses in the treatment of CD19-positive hematological malignancies, but a significant proportion of patients do not respond or relapse eventually. As an alternative to CAR T cells, T cells can be engineered to express a tumor-targeting T cell receptor (TCR). Due to HLA restriction of TCRs, CARs have emerged as a preferred treatment moiety when targeting surface antigens, despite the fact that functional differences between engineered TCR (eTCR) T and CAR T cells remain ill-defined. Here, we compared the activity of CAR T cells versus engineered TCR T cells in targeting the B cell malignancy-associated antigen CD20 as a function of antigen exposure. We found CAR T cells to be more potent effector cells, producing higher levels of cytokines and killing more efficiently than eTCR T cells in a short time frame. However, we revealed that the increase of antigen exposure significantly impaired CAR T cell expansion, a phenotype defined by high expression of coinhibitory molecules and effector differentiation. In contrast, eTCR T cells expanded better than CAR T cells under high antigenic pressure, with lower expression of coinhibitory molecules and maintenance of an early differentiation phenotype, and comparable clearance of tumor cells.
Topics: Antigens, CD20; Humans; Immunotherapy, Adoptive; Neoplasm Recurrence, Local; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 35127255
DOI: 10.1080/2162402X.2022.2033528 -
The Quarterly Journal of Nuclear... Dec 2020In recent years, the introduction of theranostic twins for specific diagnosis and treatment in patients with neuroendocrine tumors became a nuclear medicine success... (Review)
Review
In recent years, the introduction of theranostic twins for specific diagnosis and treatment in patients with neuroendocrine tumors became a nuclear medicine success story. Cu/F labeled prostate specific membrane antigen (PSMA) for molecular imaging with PET-CT and peptide radioligand therapy with Lu labeled PSMA inhibitors will favorably become the next theranostic twins in nuclear medicine history. Ga/ Cu/F PSMA PET/CT detects metastatic prostate cancer with high diagnostic sensitivity and specificity. In addition, it can be used to select patients for radioligand therapy and evaluate therapy response. Cu-labeled radiopharmaceuticals such as Cu-PSMA, and Cu-somatostatin analogs are promising imaging tools in the assessment of primary disease and also in the detection of disease recurrence and to evaluate therapy response. The long half-life of Cu allows the distribution of the tracer to PET centers as a satellite concept, who otherwise has no access to Ga generators.
Topics: Animals; Antigens, Surface; Copper Radioisotopes; Fluorine; Gallium Radioisotopes; Glutamate Carboxypeptidase II; Humans; Male; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Peptides; Positron Emission Tomography Computed Tomography; Prostatic Neoplasms; Radiopharmaceuticals; Tomography, X-Ray Computed
PubMed: 33045822
DOI: 10.23736/S1824-4785.20.03311-7 -
Current Issues in Molecular Biology Sep 2021Dexpanthenol (D-panthenol) is a precursor of vitamin B5 (pantothenic acid) and is widely used for dietary supplements and topical applications. D-panthenol has long been...
Dexpanthenol (D-panthenol) is a precursor of vitamin B5 (pantothenic acid) and is widely used for dietary supplements and topical applications. D-panthenol has long been used in hair care products for the purpose of anti-hair loss, its effects and the underlying mechanisms, however, were barely reported. In this study, the effects of D-panthenol on human hair follicle cells, including dermal papilla cells (hDPCs) and outer root sheath cells (hORSCs), were investigated. D-panthenol enhanced the cell viability, increasing the cellular proliferation marker Ki67 in cultured hDPCs. The markers for apoptosis (Caspase3/9) and cell senescence (p21/p16), reported to be expressed in aged or resting phase follicles, were significantly reduced by D-panthenol. Anagen-inducing factors (ALP; β-catenin; versican), which trigger or elongate the anagen phase, were stimulated by D-panthenol. On the other hand, D-panthenol reduced TGF-β1 expressions in both mRNA and protein levels. The expression of VEGF, which is important for peripheral blood vessel activation; was up-regulated by D-panthenol treatment. In cultured hORSCs, cell proliferation and viability were enhanced, while the mRNA expression of cell senescence markers (p21/p16) was significantly down-regulated. The expressions of both VEGF and its receptor (VEGFR) were up-regulated by D-panthenol. In conclusion, our data suggest that the hair growth stimulating activity of D-panthenol was exerted by increasing the cell viability, suppressing the apoptotic markers, and elongating the anagen phase in hair follicles.
Topics: Antigens, Surface; Apoptosis; Biomarkers; Cell Proliferation; Cells, Cultured; Cellular Senescence; Gene Expression; Gene Expression Regulation; Hair Follicle; Humans; Pantothenic Acid; RNA, Messenger; Vitamin B Complex
PubMed: 34698060
DOI: 10.3390/cimb43030097