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1.
FASEB J ; 38(10): e23644, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38738472

RESUMO

Tumors typically lack canonical danger signals required to activate adaptive immunity and also frequently employ substantial immunomodulatory mechanisms that downregulate adaptive responses and contribute to escape from immune surveillance. Given the variety of mechanisms involved in shielding tumors from immune recognition, it is not surprising that single-agent immunomodulatory approaches have been largely unsuccessful in generating durable antitumor responses. Here we report a unique combination of immunomodulatory and cytostatic agents that recondition the tumor microenvironment and eliminate complex and/or poor-prognosis tumor types including the non-immunogenic 4T-1 model of TNBC, the aggressive MOC-2 model of HNSCC, and the high-risk MYCN-amplified model of neuroblastoma. A course of therapy optimized for TNBC cured a majority of tumors in both ectopic and orthotopic settings and eliminated metastatic spread in all animals tested at the highest doses. Immune responses were transferable between therapeutic donor and naïve recipient through adoptive transfer, and a sizeable abscopal effect on distant, untreated lesions could be demonstrated experimentally. Similar results were observed in HNSCC and neuroblastoma models, with characteristic remodeling of the tumor microenvironment documented in all model systems. scRNA-seq analysis implicated upregulation of innate immune responses and antigen presentation in tumor cells and the myeloid cell compartment as critical early events. This analysis also highlighted the potential importance of the autonomic nervous system in the governance of inflammatory processes. The data indicate that the targeting of multiple pathways and mechanisms of action can result in substantial synergistic antitumor effects and suggest follow-up in the neoadjuvant setting may be warranted.


Assuntos
Microambiente Tumoral , Animais , Camundongos , Microambiente Tumoral/imunologia , Linhagem Celular Tumoral , Neuroblastoma/imunologia , Neuroblastoma/terapia , Neuroblastoma/patologia , Feminino , Humanos , Imunomodulação , Camundongos Endogâmicos C57BL
2.
Int J Mol Sci ; 25(6)2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38542184

RESUMO

Pancreatic cancer is a lethal disease, harboring a five-year overall survival rate of only 13%. Current treatment approaches thus require modulation, with attention shifting towards liberating the stalled efficacy of immunotherapies. Select chemotherapy drugs which possess inherent immune-modifying behaviors could revitalize immune activity against pancreatic tumors and potentiate immunotherapeutic success. In this study, we characterized the influence of gemcitabine, a chemotherapy drug approved for the treatment of pancreatic cancer, on tumor antigen presentation by human leukocyte antigen class I (HLA-I). Gemcitabine increased pancreatic cancer cells' HLA-I mRNA transcripts, total protein, surface expression, and surface stability. Temperature-dependent assay results indicated that the increased HLA-I stability may be due to reduced binding of low affinity peptides. Mass spectrometry analysis confirmed changes in the HLA-I-presented peptide pool post-treatment, and computational predictions suggested improved affinity and immunogenicity of peptides displayed solely by gemcitabine-treated cells. Most of the gemcitabine-exclusive peptides were derived from unique source proteins, with a notable overrepresentation of translation-related proteins. Gemcitabine also increased expression of select immunoproteasome subunits, providing a plausible mechanism for its modulation of the HLA-I-bound peptidome. Our work supports continued investigation of immunotherapies, including peptide-based vaccines, to be used with gemcitabine as new combination treatment modalities for pancreatic cancer.


Assuntos
Gencitabina , Neoplasias Pancreáticas , Humanos , Desoxicitidina/uso terapêutico , Apresentação de Antígeno , Neoplasias Pancreáticas/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Peptídeos , Antígenos de Neoplasias/uso terapêutico , Hormônios Pancreáticos , Linhagem Celular Tumoral
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