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Interferon gamma-independent rejection of interleukin 12-transduced carcinoma cells requires CD4+ T cells and
C Zilocchi1, A Stoppacciaro, C Chiodoni
1Division of Experimental Oncology D, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy.
Abstract:
We analyzed the ability of interferon (IFN)-gamma knockout mice (GKO) to reject a colon carcinoma transduced with interleukin (IL)-12 genes (C26/IL-12). Although the absence of IFN-gamma impaired the early response and reduced the time to tumor onset in GKO mice, the overall tumor take rate was similar to that of BALB/c mice. In GKO mice, C26/IL-12 tumors had a reduced number of infiltrating leukocytes, especially CD8 and natural killer cells. Analysis of the tumor site, draining nodes, and spleens of GKO mice revealed reduced expression of IFN- inducible protein 10 and monokine induced by gamma-IFN. Despite these defects, GKO mice that rejected C26/IL-12 tumor, and mice that were primed in vivo with irradiated C26/IL-12 cells, showed the same cytotoxic T lymphocyte activity but higher production of granulocyte/macrophage colony-stimulating factor (GM-CSF) as compared with control BALB/c mice. Treatment with monoclonal antibodies against GM-CSF abrogated tumor regression in GKO but not in BALB/c mice. CD4 T lymphocytes, which proved unnecessary or suppressive during rejection of C26/IL-12 cells in BALB/c mice, were required for tumor rejection in GKO mice. CD4 T cell depletion was coupled with a decline in GM-CSF expression by lymphocytes infiltrating the tumors or in the draining nodes, and with the reduction and disappearance of granulocytes and CD8 T cells, respectively, in tumor nodules. These results suggest that GM-CSF can substitute for IFN-gamma in maintaining the CD8-polymorphonuclear leukocyte cross-talk that is a hallmark of tumor rejection.
Insights
Interferon-gamma knockout mice showed impaired early tumor response but could reject tumors with the help of granulocyte/macrophage colony-stimulating factor (GM-CSF). GM-CSF substituted for interferon-gamma in tumor rejection, highlighting its role in immune responses.
Area of Science:
- Immunology
- Cancer Research
- Oncology
Background:
- Interferon-gamma (IFN-γ) plays a critical role in anti-tumor immunity.
- The role of IFN-γ in the rejection of tumors engineered to express interleukin-12 (IL-12) is not fully understood.
Purpose of the Study:
- To investigate the role of IFN-γ in the rejection of colon carcinoma cells engineered to express IL-12 (C26/IL-12).
- To explore the potential compensatory mechanisms for IFN-γ in anti-tumor immunity.
Main Methods:
- Utilized interferon-gamma knockout (GKO) mice and wild-type BALB/c mice.
- Administered C26/IL-12 colon carcinoma cells and analyzed tumor growth and immune cell infiltration.
- Assessed immune cell populations, cytokine expression (IFN-γ-inducible protein 10, monokine induced by gamma-IFN), and cytotoxic T lymphocyte activity.
- Investigated the role of granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD4 T lymphocytes in tumor rejection.
Main Results:
- GKO mice exhibited delayed tumor onset but similar overall tumor take rates compared to BALB/c mice.
- Tumors in GKO mice showed reduced infiltration of CD8 and natural killer cells, and lower expression of IFN-γ-inducible chemokines.
- Despite IFN-γ deficiency, GKO mice that rejected tumors showed increased GM-CSF production.
- GM-CSF neutralization abrogated tumor regression in GKO mice, while CD4 T cells became essential for tumor rejection in these mice.
Conclusions:
- GM-CSF can functionally substitute for IFN-γ in mediating tumor rejection, particularly in the context of CD8 T cell and polymorphonuclear leukocyte interactions.
- CD4 T cells are crucial for tumor rejection in the absence of IFN-γ, likely through their role in promoting GM-CSF production.
- These findings reveal a novel compensatory pathway in anti-tumor immunity involving GM-CSF and CD4 T cells.