Host Anti-tumor Immune Reaction during Multistage Carcinogenesis

in Japanese

Immune surveillance mechanisms work effectively during early carcinogenesis, but do not seem to work against advanced cancer. Thus, the host anti-tumor immune reaction is thought to change from one of immune surveillance to immune tolerance. In order to reach a better understanding of tumor immunology and to develop new immunotherapies, it is important to elucidate how host immune responses are changed in this way, and how a tumor begins to escape from host immune attack during carcinogenesis.

Fig. 1: Histology of human normal and neoplastic pancreatic tissues. Arrow heads indicate epithelial cells of pancreatic duct (left), adenoma cells in intraductal papillary-mucinous adenoma (middle), and adenocarcioma cells in ductal carcinoma of the pancreas (right).

Comparison of these three photo-figures reveals a change in the stroma, in addition to increasing atypism of epithelial cells during progression of carcinogenesis (Fig. 1). These morphological differences in the stroma represent alterations in the characteristics of the microenvironment, due to quantitative and qualitative changes in the constituent cells and extracellular matrix.


Fig. 2: The prevalence of FOXP3⁺CD4⁺ regulatory T cells in tumor-infiltrating CD4⁺ T cells increases significantly during the progression of human pancreatic carcinogenesis.		Fig. 3: Overall survival curves of 198 patients with pancreatic cancer. The prognosis was significantly worse in the group of high prevalence of FOXP3⁺CD4⁺regulatory T cells group compared to the low prevalence group of FOXP3⁺CD4⁺ regulatory T cells group (P < 0.0001).

We have studied the roles of regulatory T cells in the microenvironment. We showed that the prevalence of FOXP3⁺CD4⁺ regulatory T cells in tumor-infiltrating CD4⁺ T cells significantly increased during the progression of carcinogenesis (Fig. 2) and that a high prevalence of regulatory T cells is a poor prognostic indicator (Fig. 3). It is suggested that FOXP3⁺CD4⁺ regulatory T cells play a role in negatively controlling the host immune response to pancreatic cancer from the premalignant stage to established cancer (reference 1). We also demonstrated that the increase of FOXP3⁺CD4⁺ regulatory T cells is significantly correlated to the development and progression of hepatocarcinogenesis in both hepatocellular carcinoma and intrahepatic cholangiocellular carcinoma (Fig. 4, refenrence 2).

Fig. 4: Histology of hepatocellular carcinoma (left panel) and the infiltrating FOXP3⁺CD4⁺ regulatory T cells detected by immunohistochemistry using anti-FOXP3 antibody that we established (right panel).

In order to clarify the molecular mechanisms involved in alteration of the tumor immune-microenvironment, we plan to analyze the interaction between epithelial cells and immune cells. It is anticipated that these studies will provide valuable data for explaining how anti-tumor immune responses change during the progression of carcinogenesis, and for predicting the development of tumor cells or malignant transformation of premalignant lesions, detection of malignancy at an early stage, and establishment of new immunotherapy.

References
1. Clin Cancer Res, 12: 5423-5434, 2006.
2. Clin Cancer Res, 13: 902-911, 2007.

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