CD40 ligation restores cytolytic T lymphocyte response and eliminates fibrosarcoma in the peritoneum of mice lacking CD4+ T cells

Andrew Lodge, Ping Yu, Michael B. Nicholl, Ian Elliott Brown, Carl Christian A Jackson, Karin Schreiber, Sonia L. Sugg, Hans Schreiber, Joel Shilyansky

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Absence of CD4+ T cell help has been suggested as a mechanism for failed anti-tumor cytotoxic T lymphocytes (CTL) response. We examined the requirement for CD4+ T cells to eliminate an immunogenic murine fibrosarcoma (6132A) inoculated into the peritoneal cavity. Immunocompetent C3H mice eliminated both single and repeat intraperitoneal (IP) inoculums, and developed high frequency of 6132A-specific interferon-γ (IFNγ)-producing CTL in the peritoneal cavity. Adoptive transfer of peritoneal exudate cells (PEC) isolated from control mice, protected SCID mice from challenge with 6132A. In contrast, CD4 depleted mice had diminished ability to eliminate tumor and succumbed to repeat IP challenges. Mice depleted of CD4+ T cells lacked tumor-specific IFNγ producing CTL in the peritoneal cavity. Adoptive transfer of PEC from CD4 depleted mice failed to protect SCID mice from 6132A. However, splenocytes isolated from same CD4 depleted mice prevented tumor growth in SCID mice, suggesting that 6132A-specific CTL response was generated, but was not sustained in the peritoneum. Treating CD4 depleted mice with agonist anti-CD40 antibody, starting on days 3 or 8 after initiating tumor challenge, led to persistence of 6132A-specific IFNγ producing CTL in the peritoneum, and eliminated 6132A tumor. The findings suggest that CTL can be activated in the absence of CD4 + T cells, but CD4+ T cells are required for a persistent CTL response at the tumor site. Exogenous stimulation through CD40 can restore tumor-specific CTL activity to the peritoneum and promote tumor clearance in the absence of CD4+ T cells.

Original languageEnglish (US)
Pages (from-to)1542-1552
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume55
Issue number12
DOIs
StatePublished - Dec 2006
Externally publishedYes

Fingerprint

Fibrosarcoma
Peritoneum
Cytotoxic T-Lymphocytes
Ligation
T-Lymphocytes
Neoplasms
SCID Mice
Peritoneal Cavity
Interferons
Adoptive Transfer
Exudates and Transudates
Inbred C3H Mouse
Anti-Idiotypic Antibodies
Growth

Keywords

  • CD4
  • CD40
  • CD8
  • Cytotoxicity
  • T cell activation
  • T cells
  • Tumor immunity

ASJC Scopus subject areas

  • Cancer Research
  • Immunology
  • Oncology

Cite this

CD40 ligation restores cytolytic T lymphocyte response and eliminates fibrosarcoma in the peritoneum of mice lacking CD4+ T cells. / Lodge, Andrew; Yu, Ping; Nicholl, Michael B.; Brown, Ian Elliott; Jackson, Carl Christian A; Schreiber, Karin; Sugg, Sonia L.; Schreiber, Hans; Shilyansky, Joel.

In: Cancer Immunology, Immunotherapy, Vol. 55, No. 12, 12.2006, p. 1542-1552.

Research output: Contribution to journalArticle

Lodge, Andrew ; Yu, Ping ; Nicholl, Michael B. ; Brown, Ian Elliott ; Jackson, Carl Christian A ; Schreiber, Karin ; Sugg, Sonia L. ; Schreiber, Hans ; Shilyansky, Joel. / CD40 ligation restores cytolytic T lymphocyte response and eliminates fibrosarcoma in the peritoneum of mice lacking CD4+ T cells. In: Cancer Immunology, Immunotherapy. 2006 ; Vol. 55, No. 12. pp. 1542-1552.
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AU - Yu, Ping

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AU - Brown, Ian Elliott

AU - Jackson, Carl Christian A

AU - Schreiber, Karin

AU - Sugg, Sonia L.

AU - Schreiber, Hans

AU - Shilyansky, Joel

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AB - Absence of CD4+ T cell help has been suggested as a mechanism for failed anti-tumor cytotoxic T lymphocytes (CTL) response. We examined the requirement for CD4+ T cells to eliminate an immunogenic murine fibrosarcoma (6132A) inoculated into the peritoneal cavity. Immunocompetent C3H mice eliminated both single and repeat intraperitoneal (IP) inoculums, and developed high frequency of 6132A-specific interferon-γ (IFNγ)-producing CTL in the peritoneal cavity. Adoptive transfer of peritoneal exudate cells (PEC) isolated from control mice, protected SCID mice from challenge with 6132A. In contrast, CD4 depleted mice had diminished ability to eliminate tumor and succumbed to repeat IP challenges. Mice depleted of CD4+ T cells lacked tumor-specific IFNγ producing CTL in the peritoneal cavity. Adoptive transfer of PEC from CD4 depleted mice failed to protect SCID mice from 6132A. However, splenocytes isolated from same CD4 depleted mice prevented tumor growth in SCID mice, suggesting that 6132A-specific CTL response was generated, but was not sustained in the peritoneum. Treating CD4 depleted mice with agonist anti-CD40 antibody, starting on days 3 or 8 after initiating tumor challenge, led to persistence of 6132A-specific IFNγ producing CTL in the peritoneum, and eliminated 6132A tumor. The findings suggest that CTL can be activated in the absence of CD4 + T cells, but CD4+ T cells are required for a persistent CTL response at the tumor site. Exogenous stimulation through CD40 can restore tumor-specific CTL activity to the peritoneum and promote tumor clearance in the absence of CD4+ T cells.

KW - CD4

KW - CD40

KW - CD8

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