Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo
| Autor: | Jedd D. Wolchok, Margaret K. Callahan, Rakesh Verma, Kavita M. Dhodapkar, Harriet M. Kluger, Chandra Sekhar Boddupalli, Mario Sznol, Rituparna Das, Scott N. Gettinger, Ruth Halaban, Madhav V. Dhodapkar |
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| Rok vydání: | 2015 |
| Předmět: |
Combination therapy
T cell Programmed Cell Death 1 Receptor Immunology chemical and pharmacologic phenomena Biology Article Immunophenotyping Lymphocytes Tumor-Infiltrating Immune system Antigen T-Lymphocyte Subsets In vivo Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Humans Immunology and Allergy CXCL10 CTLA-4 Antigen Gene Expression Profiling Antibodies Monoclonal Ipilimumab Immune checkpoint Blockade Gene Expression Regulation Neoplastic Nivolumab medicine.anatomical_structure Antigens Surface Cancer research Cytokines Signal Transduction |
| Zdroj: | The Journal of Immunology. 194:950-959 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Combination therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor effects. Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects of these drugs in humans remain to be clearly defined. To better understand biologic effects of therapy, we analyzed blood/tumor tissue from 45 patients undergoing single or combination immune checkpoint blockade. We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinct genomic and functional signatures in vivo in purified human T cells and monocytes. Therapy-induced changes are more prominent in T cells than in monocytes and involve largely nonoverlapping changes in coding genes, including alternatively spliced transcripts and noncoding RNAs. Pathway analysis revealed that CTLA-4 blockade induces a proliferative signature predominantly in a subset of transitional memory T cells, whereas PD-1 blockade instead leads to changes in genes implicated in cytolysis and NK cell function. Combination blockade leads to nonoverlapping changes in gene expression, including proliferation-associated and chemokine genes. These therapies also have differential effects on plasma levels of CXCL10, soluble IL-2R, and IL-1α. Importantly, PD-1 receptor occupancy following anti–PD-1 therapy may be incomplete in the tumor T cells even in the setting of complete receptor occupancy in circulating T cells. These data demonstrate that, despite shared property of checkpoint blockade, Abs against PD-1, CTLA-4 alone, or in combination have distinct immunologic effects in vivo. Improved understanding of pharmacodynamic effects of these agents in patients will support rational development of immune-based combinations against cancer. |
| Databáze: | OpenAIRE |
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