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1.
Cancer Cell ; 41(5): 950-969.e6, 2023 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-37116489

RESUMO

In pancreatic ductal adenocarcinoma (PDAC) patients, we show that response to radiation therapy (RT) is characterized by increased IL-2Rß and IL-2Rγ along with decreased IL-2Rα expression. The bispecific PD1-IL2v is a PD-1-targeted IL-2 variant (IL-2v) immunocytokine with engineered IL-2 cis targeted to PD-1 and abolished IL-2Rα binding, which enhances tumor-antigen-specific T cell activation while reducing regulatory T cell (Treg) suppression. Using PD1-IL2v in orthotopic PDAC KPC-driven tumor models, we show marked improvement in local and metastatic survival, along with a profound increase in tumor-infiltrating CD8+ T cell subsets with a transcriptionally and metabolically active phenotype and preferential activation of antigen-specific CD8+ T cells. In combination with single-dose RT, PD1-IL2v treatment results in a robust, durable expansion of polyfunctional CD8+ T cells, T cell stemness, tumor-specific memory immune response, natural killer (NK) cell activation, and decreased Tregs. These data show that PD1-IL2v leads to profound local and distant response in PDAC.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Linfócitos T CD8-Positivos , Receptor de Morte Celular Programada 1 , Subunidade alfa de Receptor de Interleucina-2/uso terapêutico , Interleucina-2/farmacologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/radioterapia , Carcinoma Ductal Pancreático/tratamento farmacológico , Imunoterapia
2.
Eur J Immunol ; 51(3): 648-661, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33226131

RESUMO

Enterobacteriaceae are a large family of Gram-negative bacteria that includes both commensals and opportunistic pathogens. The latter can cause severe nosocomial infections, with outbreaks of multi-antibiotics resistant strains, thus being a major public health threat. In this study, we report that Enterobacteriaceae-reactive memory Th cells were highly enriched in a CCR6+ CXCR3+ Th1*/17 cell subset and produced IFN-γ, IL-17A, and IL-22. This T cell subset was severely reduced in septic patients with K. pneumoniae bloodstream infection who also selectively lacked circulating K. pneumonie-reactive T cells. By combining heterologous antigenic stimulation, single cell cloning and TCR Vß sequencing, we demonstrate that a large fraction of memory Th cell clones was broadly cross-reactive to several Enterobacteriaceae species. These cross-reactive Th cell clones were expanded in vivo and a large fraction of them recognized the conserved outer membrane protein A antigen. Interestingly, Enterobacteriaceae broadly cross-reactive T cells were also prominent among in vitro primed naïve T cells. Collectively, these data point to the existence of immunodominant T cell epitopes shared among different Enterobacteriaceae species and targeted by cross-reactive T cells that are readily found in the pre-immune repertoire and are clonally expanded in the memory repertoire.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Enterobacteriaceae/imunologia , Memória Imunológica/imunologia , Células Cultivadas , Reações Cruzadas/imunologia , Epitopos de Linfócito T/imunologia , Humanos , Interferon gama/imunologia , Interleucina-17/imunologia , Interleucinas/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th1/imunologia , Células Th17/imunologia , Interleucina 22
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