19 research outputs found
The immune checkpoint CD96 defines a distinct lymphocyte phenotype and is highly expressed on tumor-infiltrating TÂ cells
CD96 has recently been shown to be a potent immune checkpoint molecule in
mice, but a similar role in humans is not known. In this study, we provide a
detailed map of CD96 expression across human lymphocyte lineages, the
kinetics of CD96 regulation on T-cell activation and co-expression with other
conventional and emerging immune checkpoint molecules. We show that
CD96 is predominantly expressed by T cells and has a unique lymphocyte
expression proïŹle. CD96
high
T cells exhibited distinct effector functions on
activation. Of note, CD96 expression was highly correlated with T-cell markers
in primary and metastatic human tumors and was elevated on antigen-
experienced T cells and tumor-inïŹltrating lymphocytes. Collectively, these data
demonstrate that CD96 may be a promising immune checkpoint to enhance
T-cell function against human cancer and infectious diseas
Immune-neuroendocrine and metabolic disorders in human and experimental T. cruzi infection: New clues for understanding Chagas disease pathology
Studies in mice undergoing acute Trypanosoma cruzi infection and patients with Chagas disease, led to identify several immune-neuroendocrine disturbances and metabolic disorders. Here, we review relevant findings concerning such abnormalities and discuss their possible influence on disease physiopathology.Fil: GonzĂĄlez, Florencia BelĂ©n. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de InmunologĂa Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias MĂ©dicas. Instituto de InmunologĂa Clinica y Experimental de Rosario; ArgentinaFil: Villar, Silvina Raquel. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de InmunologĂa Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias MĂ©dicas. Instituto de InmunologĂa Clinica y Experimental de Rosario; ArgentinaFil: Pacini, MarĂa Florencia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de InmunologĂa Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias MĂ©dicas. Instituto de InmunologĂa Clinica y Experimental de Rosario; ArgentinaFil: Bottasso, Oscar Adelmo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de InmunologĂa Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias MĂ©dicas. Instituto de InmunologĂa Clinica y Experimental de Rosario; ArgentinaFil: Perez, Ana Rosa. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Rosario. Instituto de InmunologĂa Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias MĂ©dicas. Instituto de InmunologĂa Clinica y Experimental de Rosario; Argentin
Antibodies to neutralising epitopes synergistically block the interaction of the receptorâbinding domain of SARSâCoVâ2 to ACE 2
OBJECTIVES:
A major COVIDâ19 vaccine strategy is to induce antibodies that prevent interaction between the Spike protein's receptorâbinding domain (RBD) and angiotensinâconverting enzyme 2 (ACE2). These vaccines will also induce Tâcell responses. However, concerns were raised that aberrant vaccineâinduced immune responses may exacerbate disease. We aimed to identify minimal epitopes on the RBD that would induce antibody responses that block the interaction of the RBD and ACE2 as a strategy leading to an effective vaccine with reduced risk of inducing immunopathology.
METHODS:
We procured a series of overlapping 20âamino acid peptides spanning the RBD and asked which were recognised by plasma from COVIDâ19 convalescent patients. Identified epitopes were conjugated to diphtheriaâtoxoid and used to vaccinate mice. Immune sera were tested for binding to the RBD and for their ability to block the interaction of the RBD and ACE2.
RESULTS:
Seven putative vaccine epitopes were identified. Memory Bâcells (MBCs) specific for one of the epitopes were identified in the blood of convalescent patients. When used to vaccinate mice, six induced antibodies that bound recRBD and three induced antibodies that could partially block the interaction of the RBD and ACE2. However, when the sera were combined in pairs, we observed significantly enhanced inhibition of binding of RBD to ACE2. Two of the peptides were located in the main regions of the RBD known to contact ACE2. Of significant importance to vaccine development, two of the peptides were in regions that are invariant in the UK and South African strains.
CONCLUSION:
COVIDâ19 convalescent patients have SARSâCoVâ2âspecific antibodies and MBCs, the specificities of which can be defined with short peptides. Epitopeâspecific antibodies synergistically block RBDâACE2 interaction
CD96 Is an Immune Checkpoint That Regulates CD8(+) T-cell Antitumor Function
CD96 is a novel target for cancer immunotherapy shown to regulate NK cell effector function and metastasis. Here, we demonstrated that blocking CD96 suppressed primary tumor growth in a number of experimental mouse tumor models in a CD8(+) T cell-dependent manner. DNAM-1/ CD226, Batf3, IL12p35, and IFNg were also critical, and CD96-deficient CD8(+) T cells promoted greater tumor control than CD96sufficient CD8(+) T cells. The antitumor activity of anti-CD96 therapy was independent of Fc-mediated effector function and was more effective in dual combination with blockade of a number of immune checkpoints, including PD-1, PD-L1, TIGIT, and CTLA-4. We consistently observed coexpression of PD-1 with CD96 on CD8(+) T lymphocytes in tumor-infiltrating leukocytes both in mouse and human cancers using mRNA analysis, flow cytometry, and multiplex IHF. The combination of anti-CD96 with anti-PD-1 increased the percentage of IFNg-expressing CD8(+) T lymphocytes. Addition of anti-CD96 to anti-PD-1 and anti-TIGIT resulted in superior antitumor responses, regardless of the ability of the anti-TIGIT isotype to engage FcR. The optimal triple combination was also dependent upon CD8(+) T cells and IFNg. Overall, these data demonstrate that CD96 is an immune checkpoint on CD8(+) T cells and that blocking CD96 in combination with other immune-checkpoint inhibitors is a strategy to enhance T-cell activity and suppress tumor growth
Trypanosoma cruzi Disrupts Thymic Homeostasis by Altering Intrathymic and Systemic Stress-Related Endocrine Circuitries
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Previous issue date: 2013Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil.National University of Rosario and CONICET. Faculty of Medical Sciences. Institute of Immunology. Rosario, Argentina.National University of Rosario and CONICET. Faculty of Medical Sciences. Institute of Immunology. Rosario, Argentina.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre o Timo. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Rio de Janeiro, RJ, Brasil.We have previously shown that experimental infection caused by Trypanosoma cruzi is associated with changes in the
hypothalamus-pituitary-adrenal axis. Increased glucocorticoid (GC) levels are believed to be protective against the effects of
acute stress during infection but result in depletion of CD4+
CD8+ thymocytes by apoptosis, driving to thymic atrophy.
However, very few data are available concerning prolactin (PRL), another stress-related hormone, which seems to be
decreased during T. cruzi infection. Considering the immunomodulatory role of PRL upon the effects caused by GC, we
investigated if intrathymic cross-talk between GC and PRL receptors (GR and PRLR, respectively) might influence T. cruziinduced
thymic atrophy. Using an acute experimental model, we observed changes in GR/PRLR cross-activation related with
the survival of CD4+
CD8+ thymocytes during infection. These alterations were closely related with systemic changes,
characterized by a stress hormone imbalance, with progressive GC augmentation simultaneously to PRL reduction. The
intrathymic hormone circuitry exhibited an inverse modulation that seemed to counteract the GC-related systemic
deleterious effects. During infection, adrenalectomy protected the thymus from the increase in apoptosis ratio without
changing PRL levels, whereas an additional inhibition of circulating PRL accelerated the thymic atrophy and led to an
increase in corticosterone systemic levels. These results demonstrate that the PRL impairment during infection is not caused
by the increase of corticosterone levels, but the opposite seems to occur. Accordingly, metoclopramide (MET)-induced
enhancement of PRL secretion protected thymic atrophy in acutely infected animals as well as the abnormal export of
immature and potentially autoreactive CD4+
CD8+ thymocytes to the periphery. In conclusion, our findings clearly show that
Trypanosoma cruzi subverts mouse thymus homeostasis by altering intrathymic and systemic stress-related endocrine
circuitries with major consequences upon the normal process of intrathymic T cell development
Early Double-Negative Thymocyte Export in Trypanosoma cruzi Infection Is Restricted by Sphingosine Receptors and Associated with Human Chagas Disease
Tumor CD155 expression is associated with resistance to anti-PD1 immunotherapy in metastatic melanoma
Purpose: Resistance to anti-PD1 based immune checkpoint blockade (ICB) remains a problem for the treatment of metastatic melanoma. Tumor cells as well as host myeloid cells can express the immune checkpoint ligand CD155 to regulate immune cell function. However, the effect of tumor CD155 on the immune context of human melanoma has not been well described. This observational study characterizes tumor CD155 ligand expression by metastatic melanoma tumors and correlates results with differences in immune cell features and response to ICB. Experimental Design: Pre-treatment tumor specimens, from 155 metastatic melanoma patients treated with ICB and from 50 patients treated with BRAF/MEK-directed-targeted therapy, were assessed for CD155 expression by immunohistochemistry. Intratumor T cell features were analysed using multiplex-immunohistofluorescence for CD8, PD1 and SOX10. Correlations were made between CD155 tumor level and bulk tumor RNA-seq results, as well as clinical RECIST response and progression-free survival. Results: High pretreatment CD155 tumor levels correlated with high parenchymal PD1+CD8+/CD8+ T cell ratios (PD1tR) and poor response to anti-PD1 therapy. In PD-L1 negative tumors, high CD155 tumor expression was associated with patients who had poor response to combination anti-PD1/CTLA4 therapy. Conclusions: Our findings are the first to suggest that tumor CD155 supports an increase in the fraction of PD1+CD8+ T cells in anti-PD1 refractory melanoma tumors and, further, that targeting the CD155 pathway might improve response to anti-PD1 therapy for metastatic melanoma patients