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

Juan Dubrot, Francisca Milheiro, Carlos Alfaro, Asis Palazón, Ivan Martinez-Forero, Jose L. Perez-Gracia, Aizea Morales-Kastresana, José L. Romero-Trevejo, María C. Ochoa, Sandra Hervás-Stubbs, Jesús Prieto, Maria Jure-Kunkel, Lieping Chen, Ignacio Melero

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1223-1233
Number of pages11
JournalCancer Immunology Immunotherapy
Volume59
Issue number8
DOIs
StatePublished - Aug 2010

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T-Lymphocytes
Liver
Neoplasms
Therapeutics
Cholestasis
Transaminases
Immunotherapy
Histology
Flow Cytometry
Colon
Leukocytes
Color
Lymphocytes
Inflammation
Carcinoma

Keywords

  • CD137 (4-1BB)
  • Immunostimulatory monoclonal antibodies
  • Liver

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy

Cite this

Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ. / Dubrot, Juan; Milheiro, Francisca; Alfaro, Carlos; Palazón, Asis; Martinez-Forero, Ivan; Perez-Gracia, Jose L.; Morales-Kastresana, Aizea; Romero-Trevejo, José L.; Ochoa, María C.; Hervás-Stubbs, Sandra; Prieto, Jesús; Jure-Kunkel, Maria; Chen, Lieping; Melero, Ignacio.

In: Cancer Immunology Immunotherapy, Vol. 59, No. 8, 08.2010, p. 1223-1233.

Research output: Contribution to journalArticle

Dubrot, J, Milheiro, F, Alfaro, C, Palazón, A, Martinez-Forero, I, Perez-Gracia, JL, Morales-Kastresana, A, Romero-Trevejo, JL, Ochoa, MC, Hervás-Stubbs, S, Prieto, J, Jure-Kunkel, M, Chen, L & Melero, I 2010, 'Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ', Cancer Immunology Immunotherapy, vol. 59, no. 8, pp. 1223-1233. https://doi.org/10.1007/s00262-010-0846-9
Dubrot, Juan ; Milheiro, Francisca ; Alfaro, Carlos ; Palazón, Asis ; Martinez-Forero, Ivan ; Perez-Gracia, Jose L. ; Morales-Kastresana, Aizea ; Romero-Trevejo, José L. ; Ochoa, María C. ; Hervás-Stubbs, Sandra ; Prieto, Jesús ; Jure-Kunkel, Maria ; Chen, Lieping ; Melero, Ignacio. / Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ. In: Cancer Immunology Immunotherapy. 2010 ; Vol. 59, No. 8. pp. 1223-1233.
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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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T1 - Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ

AU - Dubrot, Juan

AU - Milheiro, Francisca

AU - Alfaro, Carlos

AU - Palazón, Asis

AU - Martinez-Forero, Ivan

AU - Perez-Gracia, Jose L.

AU - Morales-Kastresana, Aizea

AU - Romero-Trevejo, José L.

AU - Ochoa, María C.

AU - Hervás-Stubbs, Sandra

AU - Prieto, Jesús

AU - Jure-Kunkel, Maria

AU - Chen, Lieping

AU - Melero, Ignacio

PY - 2010/8

Y1 - 2010/8

N2 - 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.

AB - 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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KW - Immunostimulatory monoclonal antibodies

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