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Mechanisms of tumor-induced immunosuppression: evidence for contact-dependent T cell suppression by monocytes
1Department of Internal Medicine, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor 48109, USA.
Background:
The progressive growth of tumors in mice is accompanied by down-regulation of specific T cell responses. The factors involved in this suppression are not completely understood. Here, we have developed a model to examine the role of host immune effector cells in the inhibition of T cell function. In this model, progressive growth of a colon carcinoma line, CT26, is accompanied by loss of T cell response to alloantigens in both cytolytic and proliferation assays.
Materials And Methods:
The CT26 tumor was inoculated into BALB/c syngeneic mice. Tumor growth, cytolytic T cell responses, lymphocyte proliferation, and flow cytometric analysis was performed in tumor-bearing animals 7 or 28 days after tumor inoculation.
Results:
Spleen cells from tumor-bearing mice were found to suppress the proliferative response of spleen cells from normal mice to alloantigens. Examination of the spleen cell population by FACS analysis revealed an increase in the percentage of monocytes as defined by expression of CD11b, the Mac-1 antigen. Removal of the Mac-1-positive cells from the tumor-bearing hosts spleen relieved suppression of the tumor-bearing mouse spleen cell proliferative response to alloantigens, and addition of the Mac-1-positive enriched cells suppressed proliferation of normal T cells in response to alloantigens. Cell contact was required for this inhibition.
Conclusions:
Tumor induction of suppressive monocytes plays an important role in the general immunosuppression noted in animals bearing CT26 tumors. Identification of the mechanisms responsible for this effect and reversal of tumor-induced macrophage suppression may facilitate efforts to develop effective immunotherapy for malignancy.
Insights
Tumor growth in mice suppresses T cell responses by increasing suppressive monocytes. Removing these monocytes restores T cell function, suggesting a target for cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Tumor progression often correlates with suppressed T cell immunity.
- The specific immune cells responsible for this immunosuppression remain unclear.
- A model using CT26 colon carcinoma in mice was developed to study T cell inhibition.
Purpose of the Study:
- To investigate the role of host immune effector cells in T cell suppression during tumor growth.
- To identify the mechanisms behind the loss of T cell response to alloantigens in tumor-bearing mice.
Main Methods:
- CT26 colon carcinoma cells were inoculated into BALB/c mice.
- Tumor growth, T cell cytotoxicity, and lymphocyte proliferation were assessed.
- Flow cytometry (FACS) was used to analyze spleen cell populations, specifically monocytes (CD11b+).
Main Results:
- Spleen cells from tumor-bearing mice suppressed normal T cell proliferation.
- FACS analysis showed an increased percentage of CD11b-positive monocytes in tumor-bearing mice.
- Depleting CD11b+ cells from tumor-bearing mice restored T cell proliferation; adding these cells suppressed normal T cell proliferation.
Conclusions:
- Tumor-induced monocytes (Mac-1+) are key mediators of immunosuppression in CT26 tumor-bearing mice.
- Understanding and reversing this monocyte-mediated suppression could lead to improved cancer immunotherapies.