Abstract
The concept of tumor immune surveillance has been supported by several recent studies in mice which show that immune effector mechanisms suppress hematologic malignancy. However, because the most common forms of human cancer are epithelial in origin, and comparatively very little data supports the immune surveillance of epithelial malignancies, we have chosen to evaluate the role of perforin-mediated cytotoxicity in the prevention of BALB/c Her2/neu-induced mammary cancer. Interestingly, perforin significantly delayed the onset of mammary tumorigenesis and reduced the number of mammary tumors without improving survival. Natural killer cell, but not CD8+ T cell, depletion resulted in a similar phenotype to perforin deficiency in this regard. Histologic analysis further indicated that the effect of perforin was most evident during the earliest stages of carcinogenesis rather than prior to or during the hyperplastic phase. This data suggests that perforin may mediate some suppression of epithelial carcinogenesis by intervening early in the tumor development process.
Highlights
Until recently, immune surveillance was considered irrelevant for tumor development and only cancers with a viral etiology seemed to be suitable targets for immune-based cancer therapies
Because there is little evidence for immune surveillance of epithelial malignancies with nonviral etiologies, we sought to investigate this possibility by comparing mammary carcinogenesis in BALB/c Her2/neu pfp+/+ mice, BALB/c Her2/neu pfp+/À mice, and BALB/c Her2/neu pfpÀ/À mice
We sought to investigate this possibility by comparing mammary carcinogenesis in BALB/c Her2/neu mice treated with control immunoglobulins, compared with those depleted of natural killer (NK) cells or CD8+ T cells
Summary
Immune surveillance was considered irrelevant for tumor development and only cancers with a viral etiology seemed to be suitable targets for immune-based cancer therapies. With the emergence of suitable tumor antigens on epithelial cancers, genetargeting technology in mice, and neutralizing monoclonal antibodies (mAb) specific for immune effector molecules and lymphocyte subsets, our understanding of the immune system has blossomed and the involvement of the immune system in the process of carcinogenesis is once again being explored [1,2,3]. The importance of immune molecules such as perforin (pfp) and IFN-g in controlling hematologic malignancies have been established [10, 12,13,14,15], and several reports showing the importance of IFN-g in the immune surveillance of spontane-. Phone: 61-39656-3728; Fax: 61-39656-1411; E-mail: mark.smyth@ petermac.org
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