Expression of Tumor-Associated Differentiation Antigens, MUC1 Glycoforms and CEA, in Human Thymic Epithelial Cells: Implications for Self-Tolerance and Tumor Therapy

Abstract

Expression of tissue-restricted self-antigens in the thymus, termed promiscuous gene expression, imposes T cell tolerance and protects from autoimmune diseases. This antigen pool also includes various types of tumor-associated antigens (TAA) previously thought to be secluded from the immune system. The scope of promiscuous gene expression has been defined by mRNA analysis at the global level of isolated medullary thymic epithelial cells (mTECs). Information at the protein level on the frequency of mTECs expressing a given antigen, on coexpression patterns, and post-translational modifications is largely missing. We report here promiscuous expression at the protein level of two TAA, MUC1 and CEA, in situ and in purified human mTECs. Both antigens are expressed in 1% to 3% of mTECs, either individually or coexpressed in the same cell. Using a panel of anti-MUC1 monoclonal antibodies recognizing different post-translational modifications, i.e., glycoforms of MUC1, we show that only fully glycosylated forms of MUC1 and the differentiation-dependent glycoforms were detected on mTECs, but not the cancerassociated glycoforms. Our findings imply that MUC1 and CEA are amenable to central tolerance induction, which might, however, be incomplete in case of tumor cell-restricted MUC1 glycoforms. Knowledge of these subtleties in promiscuous gene expression may, in the future, assist the selection of T cell tumor vaccines for clinical trials. [Cancer Res 2007;67(8):3919-26]

Peripheral T Cells Re-Enter the Thymus and Interfere with Central Tolerance Induction

“…Therefore, thymus-re-entering T cells could also play beneficial roles in therapies, such as the highly successful adoptive transfer of tumor-specific T cells in immunedepleted cancer patients (53); tumor-specific T cells are adoptively transferred into lymphopenic cancer patients, where they expand, gain effector functions, and are able to remove tumor cells with high efficiency (53). Because thymic DCs and mTECs present tumor (self-)Ags (54,55), their possible removal might positively enhance the endogenous antitumor repertoire of the patients, similar to the appearance of OVA-specific T cells in our mouse model system (Fig. 5).…”

Ovarian cancer: Origin and factors involved in carcinogenesis with potential use in diagnosis, treatment and prognosis of the disease

“…The first one suggests that immune rejection of the tumor does not occur due to fact the tumor is recognized as immunologically normal tissue. Tumor cells express tumor-associated antigens (TAA), which can be normally present on host cells, so induction of an effective anti-tumor immune response is not achieved [120,121]. In ovarian cancer, it has been demonstrated that loss of HLA class I antigen on tumor cells correlates with poor outcome, as the interaction of T cells and the HLA receptor is needed to elicit their function (see [122]).…”

Harnessing the immune response to treat cancer

“…Tumour-associated antigens include cancer-testis antigens, for example, MAGE and ESO; differentiation antigens, such as tyrosinase, which are also expressed in the tissue of origin; oncofetal antigens such as aFP and CEA or overexpressed proteins such as Her2 or wild-type p53 (Antonia et al, 2006;Cloosen et al, 2007;van der Bruggen, 2009;Bioley et al, 2009a).…”

“…In a similar manner, tumour antigens of the cancer-testis group are largely hidden from developing immune cells. In contrast, most other tumour-associated antigens are expressed in other tissues, including the thymus (Cloosen et al, 2007), resulting in a lymphocyte population that is either deleted or has low affinity for these antigens.…”

“…However, the T-cell repertoire for tumour-associated antigens is often weak (Cloosen et al, 2007) and tumour-associated antigen targeted immunotherapy can cross-react with normal tissues, inducing autoimmunity (Gilboa, 2001;Dudley et al, 2002). …”