Using IBD and CACC as a paradigm for chronic inflammation-associated carcinogenesis, and MUC1+
mice, a new mouse model that spontaneously develops these diseases, we show that inflammation can be controlled and cancer prevented by strengthening adaptive immunity against an antigen that is known to be present at the disease site (the IBD affected colon) and on the future malignancy (CACC). We and others have previously shown that abnormal MUC1 expression is not limited to fully transformed cells, but that it can also be seen in chronic inflammation (8
). Thus in addition to being a tumor associated antigen, abnormal MUC1 is also an IBD associated antigen. We also previously reported that in the well-established IL10−/−
mouse model of IBD, addition of MUC1 expression had an enhancing effect on IBD development, degree of inflammation and progression to CACC (8
). This demonstrated that abnormal MUC1 expression was not only a marker, but also an active participant in the disease that could perpetuate chronic inflammation and drive cancer development at the disease site. In the current study, we used MUC1 as the IBD- associated antigen and a MUC1 vaccine to elicit and deliver adaptive immune response (anti-MUC1) to the site of chronic inflammation (e.g. IBD), otherwise characterized primarily by the presence of innate immune effectors. By changing the balance of innate and adaptive immunity at the disease site, we expected to change the nature of ongoing inflammation and alter the course of IBD as well as its cancer promoting potential.
We clearly show that vaccinated mice have a very different outcome than the controls in the course of their IBD, showing lesser inflammation and longer time to clinical disease. Furthermore, the controls progress to dysplasia and cancer and the vaccinated mice do not. Our data suggest that this may be the result of two different mechanisms, one a direct effector mechanism mediated by MUC1-specific adaptive immunity (anti-MUC1 IgG, MUC1-specific CTL) that appears to eliminate abnormal cells marked by abnormal expression of MUC1, and the other an indirect mechanism resulting from the changes in the local and systemic microenvironments. Locally, the pro-tumor environment of the inflamed colon, characterized by an ever-increasing neutrophil infiltration, appears to be replaced in vaccinated mice by an environment where neutrophils decrease and mononuclear cells dominate. Similarly, the systemic pro-tumor environment in the mouse with IBD, characterized by an ever-increasing number of MDSC in the spleen, is replaced in vaccinated mice by an environment lacking these cells.
Abnormal expression of normal cellular molecules can come about through many different events that affect normal cell functions, e.g. viral and bacterial infections, acute and chronic inflammations and malignant transformation (39
). We have previously published that some events affecting epithelial cells, such as mastitis affecting the MUC1+
breast duct (36
) or mumps infection of the MUC1+
salivary gland (unpublished) could lead to abnormal expression of MUC1 and an immune response against it. This immunity furthermore correlated to a reduced lifetime risk of MUC1+
ovarian cancer (40
). The results we report here suggest that this naturally acquired anti-MUC1 immunity might also be protective of MUC1+
IBD or its progression.
In view of the accumulating evidence that cancer can result from a chronic inflammatory disorder, we can consider early stages of chronic inflammation as a premalignant condition. Many molecules that are abnormally expressed in chronically inflamed tissues and the malignancies that arise from those tissues may be playing a significant role in both diseases and thus can be effectively used as targets for immunotherapy of chronic inflammation and prevention of cancer. In particular we show that during the early stages of chronic inflammation, it might be feasible to change the maladaptive tumor-promoting microenvironment to one that is tumor-inhibiting by vaccinating to induce adaptive immune responses specific for one or more disease-associated molecules.