RESUMO
Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance1,2. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity3-6. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8+ T cell function by enhancing JAK-STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.
Assuntos
Imunoterapia , Neoplasias , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteína Tirosina Fosfatase não Receptora Tipo 2 , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico , Imunoterapia/métodos , Interferons/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 2/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
In mice, hyaline droplets in renal proximal tubules have been associated with histiocytic sarcoma but have not been reported with lymphoma. Tissues from CD-1 mice in a 2-year carcinogenicity bioassay were examined microscopically. Twenty-five mice with hyaline droplets in renal tubules were identified. Immunohistochemistry to detect IgA, IgG, IgM, lysozyme, albumin, CD3, and CD79a was performed on kidneys of 21 affected mice. Hyaline droplets were present in the kidneys of 11 mice with lymphoma (1 male, 10 female), of which 1 female also had histiocytic sarcoma. Hyaline droplets were also present in 7 other mice with histiocytic sarcoma, 2 with chronic progressive nephropathy, 3 with renal cortical tubular necrosis, and 2 with granulocytic leukemia. Five of the 11 lymphomas were CD3+, indicating a T lymphocyte origin. Hyaline droplets in mice with lymphoma did not stain for IgA, IgG, or IgM, except in one questionable case. Results of other immunohistochemical stains were inconclusive. Although the droplet composition could not be determined immunohistochemically, the study findings indicate that renal tubular hyaline droplets may be associated with lymphoma in mice.
Assuntos
Hialina/metabolismo , Neoplasias Renais/metabolismo , Túbulos Renais/metabolismo , Linfoma/metabolismo , Animais , Testes de Carcinogenicidade , Modelos Animais de Doenças , Feminino , Sarcoma Histiocítico/metabolismo , Sarcoma Histiocítico/patologia , Hialina/química , Imuno-Histoquímica , Rim/química , Rim/metabolismo , Rim/patologia , Neoplasias Renais/química , Neoplasias Renais/patologia , Túbulos Renais/química , Túbulos Renais/patologia , Linfoma/química , Linfoma/patologia , Masculino , Camundongos , Camundongos Transgênicos , NecroseRESUMO
A case of a subcutaneous polypoid lipoma, presenting as a rudimentary polydactyly, is reported. The lesion was located between the first and second digits and extended into the first intermetatarsal space in a polypoid fashion. Radiographically, there were no osseous structures associated with the mass, and preliminary biopsy results showed no evidence of malignancy. The patient was treated with marginal excision of the mass and reduction of the intermetatarsal space with a Mini TightRope (Arthrex, Inc., Naples, FL). The final pathological diagnosis was polypoid lipomas, and the patient experienced a full and uneventful recovery.
Assuntos
Lipoma/patologia , Polidactilia/diagnóstico , Neoplasias Cutâneas/patologia , Tela Subcutânea/patologia , Biópsia por Agulha , Diagnóstico Diferencial , Seguimentos , Doenças do Pé/diagnóstico , Doenças do Pé/cirurgia , Humanos , Imuno-Histoquímica , Lipoma/diagnóstico , Lipoma/cirurgia , Masculino , Pessoa de Meia-Idade , Polidactilia/patologia , Medição de Risco , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/cirurgia , Tela Subcutânea/cirurgia , Articulação do Dedo do Pé , Resultado do TratamentoRESUMO
A 17-year-old Bengal tiger (Panthera tigris) presented with dyspnea and tachypnea. Radiographs revealed severe pleural and pericardial effusion, but no obvious mass. During attempts to remove the fluid under anesthesia, the cat developed cardiac tamponade and died. At necropsy, a nodular mass was found at the heart base and was identified as a pericardial mesothelioma. This is the first report of this tumor in any large cat.