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Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ

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Abstract

Background/aims

Cancer therapy with agonist anti-CD137 mAbs has been shown to induce immune-mediated tumor rejections in mice, and equivalent agents of this kind are currently being tested in cancer patients. Previous reports indicated that CD137 stimulation induced polyclonal infiltrates of T lymphocytes in the liver. This study characterizes the liver infiltrates and the target dependency of the phenomena and addresses the question of whether tumors nested in the liver are a more favorable target for CD137-based immunotherapy.

Methods

Liver infiltrates were studied with conventional histology and multiple color flow cytometry of total liver leukocytes. CD137−/− mice, mice with a single rearrangement of the TCR (OT-1 mice) and Rag−/− mice were used to clarify molecular requirements. Mice implanted with MC38 colon carcinomas either subcutaneously or inside the liver were used for comparative studies under treatment with agonist anti-CD137 mAbs.

Results

CD137 treatment caused mononuclear inflammation in the portal spaces of the liver, which gave rise to moderate increases in transaminases without signs of cholestasis. Marked increases in the numbers of CD8+ T cells were observed, including CD8+ T lymphocytes co-expressing CD11c. Infiltrates were absent in CD137−/− mice and mitigated in mice harboring a single transgenic TCR on their CD8 T cells. Despite the tumor-independent accumulation of T cells in the liver, immunotherapeutic effects were not more prominent against tumors located in this organ.

Conclusions

Target-dependent effects of CD137 stimulation lead to liver infiltration with T cells, but lymphocyte enrichment in this organ does not privilege this site for immunotherapeutic effects against transplanted tumors.

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Acknowledgments

Elena Ciordia and Eneko Elizalde are acknowledged for the excellent animal facility management. Financial support was obtained from MEC/MICINN (SAF2005-03131 and SAF2008-03294), Departamento de Educación del Gobierno de Navarra, Departamento de Salud del Gobierno de Navarra (Beca Ortiz de Landázuri). Redes temáticas de investigación cooperativa RETIC (RD06/0020/0065), Fondo de investigación sanitaria (FIS PI060932), European Commission VII Framework Program (ENCITE) and SUDOE-IMMUNONET, Fundacion Mutua Madrileña, and “UTE for project FIMA”. M S–H receives a Ramon y Cajal contract from Ministerio de Educación y Ciencia and A P a scholarship from FIS.

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Authors and Affiliations

  1. Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Av. Pio XII, 55, 31008, Pamplona, Spain

    Juan Dubrot, Francisca Milheiro, Carlos Alfaro, Asis Palazón, Ivan Martinez-Forero, Aizea Morales-Kastresana, José L. Romero-Trevejo, María C. Ochoa, Sandra Hervás-Stubbs, Jesús Prieto & Ignacio Melero

  2. Clínica Universitaria, Universidad de Navarra, Pamplona, Spain

    Jose L. Perez-Gracia, Jesús Prieto & Ignacio Melero

  3. Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA

    Maria Jure-Kunkel

  4. Sidney Kimmel Cancer Center, Johns Hopkins Medical School, Baltimore, MD, USA

    Lieping Chen

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  1. Juan Dubrot
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  14. Ignacio Melero
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Correspondence to Ignacio Melero.

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Dubrot, J., Milheiro, F., Alfaro, C. et al. Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ. Cancer Immunol Immunother 59, 1223–1233 (2010). https://doi.org/10.1007/s00262-010-0846-9

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