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Immunoregulation in cancer-bearing hosts. Down-regulation of gene expression and cytotoxic function in CD8+ T cells
C M Loeffler1, M J Smyth, D L Longo
1Immunotherapy Laboratory, Program Resources, Inc./DynCorp, Frederick, MD 21702.
Abstract:
The causes of the decreased immune responsiveness in tumor-bearing hosts are incompletely understood. The impact of a decreased immune response in cancer patients on the clinical response in immunotherapy trials has not been evaluated. The present report demonstrates a marked decrease in the therapeutic efficacy of adoptively transferred T lymphocytes obtained from murine hosts bearing tumor for greater than 30 days [late tumor-bearing mice (TBM)] as compared with normal mice and mice bearing tumor for less than 21 days (early TBM). In vitro analysis of the functions of the T lymphocytes from late TBM showed an apparently normal proliferative response to anti-CD3 and IL-2 with adequate lymphokine production from CD4+ cells, but a significant decrease in the cytotoxic function of CD8+ cells. The decreased cytotoxicity was not because of cell-mediated suppression. The expression of granzyme B mRNA was significantly delayed and decreased in magnitude in CD8+ cells from late TBM. Culture supernatants from two unrelated tumor cell lines were able to inhibit the cytotoxic activity of normal CD8+ cells in vitro. The tumor-derived suppressive factor is not transforming growth factor-beta (TGF-beta), but it has not been further characterized. The data suggest that one potential mechanism responsible for immunologic defects in patients with large tumor burdens is a tumor-induced defect that compromises the function of CD8+ effector T cells.
Insights
Tumor burden impairs T cell function, reducing immunotherapy effectiveness. Late-stage tumor-bearing mice show decreased CD8+ T cell cytotoxicity due to tumor-induced defects, impacting adoptive T cell therapy efficacy.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Immunology
Background:
- Decreased immune responsiveness in tumor-bearing hosts is poorly understood.
- The impact of impaired immune responses on immunotherapy efficacy in cancer patients remains unevaluated.
Purpose of the Study:
- To evaluate the impact of tumor burden on T lymphocyte function and therapeutic efficacy.
- To investigate the mechanisms underlying decreased immune responsiveness in late-stage tumor-bearing hosts.
Main Methods:
- Adoptive transfer of T lymphocytes from normal, early tumor-bearing mice (TBM), and late TBM.
- In vitro analysis of T lymphocyte proliferation, lymphokine production (CD4+ cells), and cytotoxic function (CD8+ cells).
- Assessment of granzyme B mRNA expression and inhibition of cytotoxic activity by tumor cell culture supernatants.
Main Results:
- Adoptively transferred T cells from late TBM showed significantly reduced therapeutic efficacy compared to those from normal or early TBM.
- CD8+ T cells from late TBM exhibited decreased cytotoxic function, despite normal proliferation and CD4+ cell lymphokine production.
- Reduced cytotoxicity was linked to delayed and decreased granzyme B mRNA expression in CD8+ cells.
- Tumor cell culture supernatants inhibited normal CD8+ cell cytotoxicity, suggesting a tumor-derived suppressive factor.
Conclusions:
- Tumor burden, particularly in late stages, compromises CD8+ effector T cell function.
- A tumor-induced defect, potentially involving a non-TGF-beta suppressive factor, contributes to immunologic defects in cancer patients.
- These findings highlight a mechanism limiting immunotherapy effectiveness in patients with large tumor burdens.