Immune response against medullary thyroid carcinoma (MTC) induced by parental and/or interleukin-2-secreting MTC cells in a rat model of human familial medullary thyroid carcinoma

Abstract

The existence of inherited aggressive forms of medullary thyroid carcinoma (MTC), and their resistance to all classical therapies, make it a prime candidate for adoptive immunotherapy. As a prelude to a vaccine for the protection of family members at risk of developing the disease, we investigated the immunological antitumour response provoked by the 6/23 rMTC cell line, compared to that of the same cell engineered to secrete interleukin-2 (rMTC-IL2), in an animal model of familial human MTC, the inbred strain of Wag/Rij rats. The rMTC cells developed a tumour that invaded the whole neck 15 days after orthotopic injection (into the thyroid), while the rMTC-IL2 cells were progressively rejected. Co-injection of rMTC-IL2 with the parental cells induced the rejection of the rMTC transplants. When injected, both tumoral cell types showed a similar positive immunoreaction with anti-MHC class I (major histocompatibility complex class I) antibodies. They both recruited natural killer cells and eosinophils at the site of injection. In addition, CD8+ T lymphocytes infiltrated the rMTC-IL2 cells, and eosinophil recruitment was amplified. Neutrophils, macrophages and CD4+ T lymphocytes were scarce. Our results suggest that the CD8+ T lymphocytes are implicated in the anti-tumour reaction elicited by the IL-2-transfected cells. As these effectors are known to induce a specific immunological response, including memory, such a protocol should be tested as a vaccine on the young population genetically at risk of developing a MTC.

Expression of laminin-2 by normal and neoplastic rat C cells during the development of medullary thyroid carcinoma

“…As already reported, this cell line is largely dedifferentiated and tumours were always immunonegative to CT antibodies [14,38]. Fifteen days after grafting, the tumour mass was encapsulated in thick multilayere connective tissue, but no staining with laminin and collagen IV antibodies was detected in the peripheral layer from 2 to 15 days after transplantation.…”

Antitumor Capacity of a Dominant-NegativeRETProto-Oncogene Mutant in a Medullary Thyroid Carcinoma Model

“…In the past, successful trials of genetic cytokine immunotherapy have emerged as a promis- ing approach for treating MTC (Lausson et al, 1996;Zhang and DeGroot, 2000b;Yamazaki et al, 2002), related to expression of tumor-associated antigens by MTC (Cressent et al, 1995). Moreover, the HSVtk-GCV system (herpes simplex virus thymidine kinase combined with concomitant application of ganciclovir) has been used to treat MTC, either alone (Minemura et al, 2000;Zhang and DeGroot, 2000a) or in combination with immunotherapy (Zhang and DeGroot, 2001).…”

Current approaches and perspectives in the therapy of medullary thyroid carcinoma

“…Tumors caused by implanted MTC cells in animals can be inhibited in their growth and even eradicated by local secretion of IL‐2. This cytokine leads to the development of antitumoral immunity by stimulating the proliferation of cytotoxic and helper T cells, causing the activation of natural killer cells and enhancing their cytolytic function as lymphokine‐activated killer cells 104–107. Conversely, severe side effects due to systemic administration of high doses of IL‐2 have limited its clinical use in the treatment of cancer .…”