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Increasing infiltration and activation of CD8+ tumor-infiltrating lymphocytes after eliminating immune suppressive granulocyte/macrophage progenitor cells with low doses of interferon γ plus tumor necrosis factor α

  • Original Articles
  • Immune-Suppressor Cells, Tumor-Infiltrating Lymphocytes, Myeloid Progenitor Cells, GM-CSF, Interferon γ, Tumor Necrosis Factor α
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

By secreting granulocyte/macrophage colonystimulating factor (GM-CSF), metastatic Lewis lung carcinoma (LLC-LN7) tumors induce the appearance of myelopoiesis-associated immune-suppressor cells that resemble granulocytic-macrophage (GM) progenitor cells. The presence of these GM-suppressor cells in mice bearing LLC-LN7 tumors was associated with a reduced capacity of splenic T cells to proliferate in response to interleukin-2 (IL-2). Administration of low doses of 100 U interferon γ (IFNγ) plus 10 U tumor necrosis factor α (TNFα) to the tumor bearers, a combination treatment that we previously showed to diminish the presence of GM-suppressor cells synergistically, restored proliferative responsiveness of the splenic T cells to IL-2. These LLC-LN7-bearing mice were also examined for whether cells that phenotypically resemble GM-progenitor cells (ER-MP12+ cells) infiltrate the tumor mass. ER-MP12+ cells composed approximately 10% of the cells isolated from dissociated tumors of mice that had been treated with placebo or with either IFNγ or TNFα alone, but IFNγ/TNFα therapy markedly reduced the number of tumor-infiltrating ER-MP12+ suppressor cells. The IFNγ/TNFα treatment to eliminate GM-suppressor cells and restore T cell responsiveness to IL-2 was next coupled with low dose IL-2 therapy (100 U twice daily). Addition of IL-2 to the treatment regimen did not significantly influence the effectiveness of the IFNγ/TNFα treatment in eliminating GM-suppressor cells from the LLC-LN7 tumor mass. However, inclusion of IL-2 with the IFNγ/TNFα treatment regimen enhanced the CD8+, but not the CD4+, cell content within the tumor, and diminished the number of metastatic lung nodules within the mice. When these tumors were excised, dissociated, and bulk-cultured with a low dose of IL-2, an increased level of cytotoxic T lymphocyte (CTL) activity was generated in the TIL cultures from mice that had received IFNγ/TNFα plus IL-2 treatments. A lesser but detectable level of CTL activity was generated in TIL cultures from mice that were treated with only IFNγ/TNFα, while no CTL activity was generated in tumor cultures from mice receiving only placebo or low-dose IL-2. These results suggest the effectiveness of IFNγ plus TNFα therapy in restoring IL-2 responsiveness in mice bearing GM-suppressor cell-inducing tumors and at enhancing both the intratumoral CD8+ cell content and the generation of CTL activity in bulk cultures of these tumors.

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Authors and Affiliations

  1. Research Service, Department of Veterans Affairs, Hines VA Hospital, 60141, Hines, IL, USA

    M. Rita I. Young & Mark A. Wright

  2. Department of Pathology, Loyola University Stritch School of Medicine, 60153, Maywood, IL, USA

    M. Rita I. Young, Gayle McCloskey & Annette Schmidt Pak

Authors
  1. M. Rita I. Young
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  2. Gayle McCloskey
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  3. Mark A. Wright
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  4. Annette Schmidt Pak
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This study was supported by the Medical Research Service of the Department of Veterans Affairs, by grants CA-45080 and CA-48080 from the National Institutes of Health, and by the American Cancer Society, Illinois

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Young, M.R.I., McCloskey, G., Wright, M.A. et al. Increasing infiltration and activation of CD8+ tumor-infiltrating lymphocytes after eliminating immune suppressive granulocyte/macrophage progenitor cells with low doses of interferon γ plus tumor necrosis factor α. Cancer Immunol Immunother 38, 9–15 (1994). https://doi.org/10.1007/BF01517164

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  • DOI: https://doi.org/10.1007/BF01517164

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