Cancer Vaccines 2004 opening address: The molecular and cellular basis of cancer immunosurveillance and immunoediting

The three Es of cancer immunoediting: host protective versus tumor sculpting actions of immunity. Following cellular transformation and the failure of intrinsic tumor suppressor mechanisms, a developing tumor is detected by the immune system and its ultimate fate is determined by whether or not it is eliminated by the host protective actions of immunity (Elimination phase), maintained in a dormant or equilibrium state (Equilibrium phase) or escapes the extrinsic tumor suppressor actions of immunity by either becoming non-immunogenic or through the elaboration of immunosuppressive molecules and cells (Escape phase) [adapted from (3)].

A plethora of data from many groups supports the existence of a cancer immunosurveillance process in mice. Support comes from the use of gene-targeted mice with congenital immunodeficiencies, as well as using adult wild type mice rendered immunodeficient by injection of neutralizing or depleting antibodies. Together this work shows that loss of either innate or adaptive immunity leads to increased carcinogen-induced and spontaneous tumors in the immunodeficient mice [adapted from (2)].

Increased formation of carcinogen-induced sarcomas in immunocompromised mice. Large groups of sex- and age-matched wild type 129 strain mice or 129 strain mice with targeted disruption of the genes for RAG2, IFNGR1 (the ligand binding subunit of the IFN-gamma receptor), STAT1 (the transcription factor critical for IFN-gamma- and IFN-alpha/beta-receptor signaling), or RAG2 plus STAT1, were treated with a 100 µg dose of the chemical carcinogen 3’-methylcholanthrene and tumor formation was followed over time. The final tumor incidences of each group is shown at 160 days [adapted from (49)].

Increased incidence of spontaneous tumors in immunodeficient mice. Eleven to twelve member cohorts of wild type 129 strain mice, or 129 strain mice lacking RAG2 or RAG2 plus STAT1 were set aside to age and tumor incidences followed. At necropsy, mice were scored as either neoplasia-free, positive for adenomatous changes (pre-malignant neoplasia) or positive for unequivocal adenocarcinomas. These results were confirmed subsequently using larger groups [adapted from (49)].

Tumors derived from immunodeficient mice are highly immunogenic. Seventeen MCA-induced sarcomas from wild type mice (panels a and c) and twenty MCA-sarcomas from RAG2^-/- mice (panels b and d) were each injected into five member groups of either immunodeficient RAG2^-/- mice (panels a and b) or naive immunocompetent wild type mice (panels c and d). Tumor growth was monitored by daily measurement of tumor size [adapted from (49)].

Rejection of IFNGR1 deficient RAD.gR.28 sarcomas following reconstitution of IFN-gamma responsiveness. An MCA sarcoma cell line (RAD.gR.28) from an IFNGR1^-/- mouse was transduced either with empty retrovirus (control), a functionally inactive IFNGR1 C-terminal truncation mutant (IFNGR1deltaIC) or wild type IFNGR1. After isolation of homogeneous transduced cell populations, groups of 5 wild type, genetically matched mice were injected with 1 x 10⁶ of each cell type. Tumor growth was quantitated by daily measurement of tumor size [adapted from (54)].

Rejection of Tap1- or H2-D^b-reconstituted IFN-gamma-insensitive RAD.gR.28 tumor cells in wild type mice. The RAD.gR.28 tumor cell line used in Figure 7, was transduced with either empty retrovirus or retroviruses encoding H2-K^b, H2-D^b or Tap1. After isolating homogeneously expressing cell lines, cells were transplanted into 5-member groups of wild type mice and tumor growth quantitated as described previously [adapted from (49)].