Immunology of naturally transmissible tumours

Abstract

Naturally transmissible tumours can emerge when a tumour cell gains the ability to pass as an infectious allograft between individuals. The ability of these tumours to colonize a new host and to cross histocompatibility barriers contradicts our understanding of the vertebrate immune response to allografts. Two naturally occurring contagious cancers are currently active in the animal kingdom, canine transmissible venereal tumour (CTVT), which spreads among dogs, and devil facial tumour disease (DFTD), among Tasmanian devils. CTVT are generally not fatal as a tumour-specific host immune response controls or clears the tumours after transmission and a period of growth. In contrast, the growth of DFTD tumours is not controlled by the Tasmanian devil's immune system and the disease causes close to 100% mortality, severely impacting the devil population. To avoid the immune response of the host both DFTD and CTVT use a variety of immune escape strategies that have similarities to many single organism tumours, including MHC loss and the expression of immunosuppressive cytokines. However, both tumours appear to have a complex interaction with the immune system of their respective host, which has evolved over the relatively long life of these tumours. The Tasmanian devil is struggling to survive with the burden of this disease and it is only with an understanding of how DFTD passes between individuals that a vaccine might be developed. Further, an understanding of how these tumours achieve natural transmissibility should provide insights into general mechanisms of immune escape that emerge during tumour evolution.

Keywords: MHC; cancer; comparative immunology/evolution; transplantation; tumour immunology.

Figure 1

Pathology of canine transmissible venereal tumour (CTVT) and devil facial tumour disease (DFTD. (a) External view of CTVT and DFTD tumours (i) a CTVT tumour at the base of the penis, (ii) a DFTD tumour on the inner lip before ulceration and, (iii) an advanced DFTD tumour that is ulcerated and disrupting dentition. CTVT image is courtesy of Dr Elizabeth Murchison and Andrea Strakova. (b) Haematoxylin & eosin stained biopsies at 40× magnification (i) CTVT and (ii) DFTD, scale bars 50 μm. CTVT image is courtesy of Andrea Strakova.

Figure 2

Current model of the interaction of canine transmissible venereal tumour (CTVT) and devil facial tumour disease (DFTD) with host immune cells. (a) CTVT progression can be characterized by growth and regression phases. During growth (i) CTVT cells lack MHC molecules and release transforming growth factor-β (TGFβ), which suppresses T cells and natural killer (NK) cells and may prevent expression of MHC. IgG coats CTVT cells and may contribute to the ability of B cells and NK cells to recognize MHC-negative CTVT cells. During regression (ii) interleukin-6 (IL-6) is released by infiltrating lymphocytes, perhaps antagonizing TGF-β. The concentration of interferon-γ (IFN-γ) increases and MHC class I and class II molecules are expressed on 40–60% of CTVT cells, leading to cytotoxicity by T cells and NK cells. (b) DFTD progression is not characterized by different phases of growth and regression, but DFTD cells are sensitive to IFN-γ. Before IFN-γ treatment (i) antigen processing and presenting genes are epigenetically down-regulated and MHC molecules are not present on DFTD cells. There are few lymphocytes infiltrating the tumour and the reason for NK cell ignorance is not known. After IFN-γ treatment (ii) DFTD cells express MHC class I and class II molecules but why this does not lead to a protective immune response is not known.