RESUMEN
TIGIT is an immune checkpoint inhibitor expressed by effector CD4+ and CD8+ T cells, NK cells, and regulatory T cells (Tregs). Inhibition of TIGIT-ligand binding using antagonistic anti-TIGIT mAbs has shown in vitro potential to restore T-cell function and therapeutic efficacy in murine tumor models when combined with an anti-PD(L)-1 antibody. In the current work, we demonstrate broader TIGIT expression than previously reported in healthy donors and patients with cancer with expression on γδ T cells, particularly in CMV-seropositive donors, and on tumor cells from hematologic malignancies. Quantification of TIGIT density revealed tumor-infiltrating Tregs as the population expressing the highest receptor density. Consequently, the therapeutic potential of anti-TIGIT mAbs might be wider than the previously described anti-PD(L)-1-like restoration of αß T-cell function. CD155 also mediated inhibition of γδ T cells, an immune population not previously described to be sensitive to TIGIT inhibition, which could be fully prevented via use of an antagonistic anti-TIGIT mAb (EOS-448). In PBMCs from patients with cancer, as well as in tumor-infiltrating lymphocytes from mice, the higher TIGIT expression in Tregs correlated with strong antibody-dependent killing and preferential depletion of this highly immunosuppressive population. Accordingly, the ADCC/ADCP-enabling format of the anti-TIGIT mAb had superior antitumor activity, which was dependent upon Fcγ receptor engagement. In addition, the anti-TIGIT mAb was able to induce direct killing of TIGIT-expressing tumor cells both in human patient material and in animal models, providing strong rationale for therapeutic intervention in hematologic malignancies. These findings reveal multiple therapeutic opportunities for anti-TIGIT mAbs in cancer therapeutics.
Asunto(s)
Anticuerpos Antineoplásicos/inmunología , Anticuerpos Antineoplásicos/farmacología , Citotoxicidad Inmunológica , Receptores Inmunológicos/antagonistas & inhibidores , Linfocitos T Reguladores/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Antígenos CD/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Femenino , Voluntarios Sanos , Humanos , Inmunoglobulina G/metabolismo , Depleción Linfocítica , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores de IgG/metabolismo , Receptores Inmunológicos/metabolismo , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
Though the ovine stifle is commonly used to study osteoarthritis, there is limited information about the age-related morphometric changes of the tidemark. The objective of this study was to document the number of tidemarks in the stifle of research sheep without clinical signs of osteoarthritis and of various ages (n = 80). Articular cartilage of the medial and lateral tibial condyles and of the medial and lateral femoral condyles was assessed by histology: (a) to count the number of tidemark; and (b) to assess the OARSI (Osteoarthritis Research Society International) score for structural changes of cartilage. The number of tidemarks varied between anatomical regions, respectively, from 4.2 in the medial femoral condyle to 5.0 in the lateral tibial condyle. The axial part showed a significant higher number of tidemarks than the abaxial part, for all regions except the medial tibial condyle. Whilst the tidemark count strongly correlated with age (Spearman's correlation coefficient = 0.70; 95% confidence interval (95% CI): 0.67-0.73; p < 0.0001), the OARSI score was weakly correlated with age in our cohort of sheep (Spearman's correlation coefficient = 0.25; 95% CI: 0.19-0.30; p < 0.0001). Interestingly, no tidemark was seen in the three animals aged 6 months. Our data indicate that the number of tidemarks increases with age and vary with anatomical region. The regional variation also revealed a higher number of tidemarks in the tibia than in the femur. This could be attributed to the local variation in cartilage response to strain and to the difference in chondrocyte biology and density.
Asunto(s)
Envejecimiento , Ovinos/crecimiento & desarrollo , Rodilla de Cuadrúpedos/crecimiento & desarrollo , Envejecimiento/fisiología , Animales , Calcificación Fisiológica/fisiología , Estudios de Cohortes , Femenino , Cartílago Hialino/anatomía & histología , Modelos AnimalesRESUMEN
Tumors use indoleamine 2,3-dioxygenase-1 (IDO1) as a major mechanism to induce an immunosuppressive microenvironment. IDO1 expression is upregulated in many cancers and considered to be a resistance mechanism to immune checkpoint therapies. IDO1 is induced in response to inflammatory stimuli such as IFNγ and promotes immune tolerance by depleting tryptophan and producing tryptophan catabolites, including kynurenine, in the tumor microenvironment. This leads to effector T-cell anergy and enhanced Treg function through upregulation of FoxP3. As a nexus for the induction of key immunosuppressive mechanisms, IDO1 represents an important immunotherapeutic target in oncology. Here, we report the identification and characterization of the novel selective, orally bioavailable IDO1 inhibitor EOS200271/PF-06840003. It reversed IDO1-induced T-cell anergy in vitro In mice carrying syngeneic tumor grafts, PF-06840003 reduced intratumoral kynurenine levels by over 80% and inhibited tumor growth both in monotherapy and, with an increased efficacy, in combination with antibodies blocking the immune checkpoint ligand PD-L1. We demonstrate that anti-PD-L1 therapy results in increased IDO1 metabolic activity thereby providing additional mechanistic rationale for combining PD-(L)1 blockade with IDO1 inhibition in cancer immunotherapies. Supported by these preclinical data and favorable predicted human pharmacokinetic properties of PF-06840003, a phase I open-label, multicenter clinical study (NCT02764151) has been initiated.