Immunotherapy of CT26 murine tumors is characterized by an oligoclonal response of tissue‐resident memory T cells against the AH1 rejection antigen
- 29 May 2020
- journal article
- research article
- Published by Wiley in European Journal of Immunology
- Vol. 50 (10), 1591-1597
- https://doi.org/10.1002/eji.201948433
Abstract
Mice bearing CT26 tumors can be cured by administration of L19‐mIL12 or F8‐mTNF, two antibody fusion proteins which selectively deliver their cytokine payload to the tumor. In both settings, cancer cures crucially depended on CD8+ T cells and the AH1 peptide (derived from the gp70 protein of the murine leukemia virus) acted as the main tumor‐rejection antigen, with ∼50% of CD8+ T cells in the neoplastic mass being AH1‐specific after therapy. In order to characterize the clonality of the T cell response, its phenotype and activation status, we isolated CD8+ T cells from tumors and submitted them to T cell receptor (TCR) and total mRNA sequencing. We found an extremely diverse repertoire of more than 40’000 unique TCR sequences, but the ten most abundant TCRs accounted for >60% of CD8+ T cell clones in the tumor. AH1‐specific TCRs were consistently found among the most abundant sequences. AH1‐specific T cells in the tumor had a tissue‐resident memory phenotype. Treatment with L19‐mIL12 led to over‐expression of interleukin‐12 receptor and of markers of cell activation and proliferation. These data suggest that the antitumor response driven by antibody‐cytokine fusions proceeds through an oligoclonal expansion and activation of tumor‐infiltrating CD8+ T cells. This article is protected by copyright. All rights reservedKeywords
Funding Information
- H2020 European Research Council (670603)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_182003/1)
This publication has 32 references indexed in Scilit:
- Genomic correlates of response to CTLA-4 blockade in metastatic melanomaScience, 2015
- Neoantigens in cancer immunotherapyScience, 2015
- Trimmomatic: a flexible trimmer for Illumina sequence dataBioinformatics, 2014
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Immunocytokines: a novel class of potent armed antibodiesDrug Discovery Today, 2012
- Paired analysis of TCRα and TCRβ chains at the single-cell level in miceJCI Insight, 2011
- edgeR: a Bioconductor package for differential expression analysis of digital gene expression dataBioinformatics, 2009
- A high‐affinity human monoclonal antibody specific to the alternatively spliced EDA domain of fibronectin efficiently targets tumor neo‐vasculature in vivoInternational Journal of Cancer, 2008
- Proprotein convertase furin is preferentially expressed in T helper 1 cells and regulates interferon gammaBlood, 2006
- The immunodominant major histocompatibility complex class I-restricted antigen of a murine colon tumor derives from an endogenous retroviral gene product.Proceedings of the National Academy of Sciences, 1996