Decreased T-Cell Proliferation and Skewed Immune Responses in LLC-Bearing Mice

Abstract

Deficits in immune cell responses have been reported in cancer patients. We used the murine Lewis lung carcinoma (LLC) model to better understand these deficits. The goal of this study was to determine if the immune responses of LLC tumor-bearing (TB) mice differ from control mice and whether the difference could be attributed to either antigen-presenting cells (FPC) or to T cells. Tumors were first allowed to grow in vivo for approximately 2 weeks. Splenocytes were then isolated for in vitro proliferation and cytokine release studies. The results showed a decrease in mitogen-stimulated proliferation by unfractionated splenocyte cultures from TB mice when compared to control mice in response to concanavalin A (Con A), a T-cell mitogen. Decreased responses were also observed when the APC spleen cell fraction from TB mice was cultured with normal T cells, although proliferation was more prominently reduced in cultures of TB T cells plus normal APC. Also, splenocytes from TB mice secreted significantly increased levels of IFN-gamma, IL-4, and IL-10. Admixing APC from control mice with TB T cells significantly decreased levels of IL-4 and IL-10 secretion as compared to the levels secreted by cocultures of TB T cells and TB APC. The decreased cytokine profile in the presence of normal APC despite the presence of TB T cells suggests that APC contributes to the immune dysfunction, including Th skewing of tumor bearers, possibly through their influence on T-cell expansion and cytokine production. Finally, our assessment of the APC population contributing to the observed immune dysfunction--i.e., dendritic cells or macrophages--showed that the proliferation of TB T cells was decreased regardless of the APC population with which they were cocultured. However, normal T-cell proliferation was only reduced by the addition of TB macrophages and not by the addition of TB dendritic cells. In conclusion, our results demonstrate that LLC TB mice have a skewed immune response characterized by a decreased proliferative response with both T cells and APC affected by the presence of tumor.