Vaccines for tumor prevention: a pipe dream?

Whether or not a tumor expresses peculiar antigens that differentiate it from normal cells was intensively investigated in the 1950s. A conclusive answer was provided in 1960 when George Klein showed that a tumor can be rejected by the immune response elicited by a vaccine administered to the same mouse in which the tumor was induced. Whether immunogenicity was a feature restricted only to tumors artificially induced by viruses or by high doses of chemical carcinogens was then hotly debated until Terry Boon showed, in the 1980s, that almost any tumor can be recognized by a syngeneic immune system triggered by an appropriate cancer vaccine. However, the therapeutic efficacy of vaccine-induced immunity against an advanced tumor is marginal. The combination of an anti-tumor vaccine with new sophisticated maneuvers to contrast tumor-induced suppression may yield new and effective therapeutic strategies. Also, the exploitation of tumor vaccines to prevent tumors in cohorts of people with a specific risk of cancer may become a fresh strategy with great potential to control tumor onset

2011: the immune hallmarks of cancer

Ten years after the publication of the position paper “The hallmarks of cancer” (Hanahan and Weinberg Cell 100:57–70, 2000), it has become increasingly clear that mutated cells on their way to giving rise to a tumor have also to learn how to thrive in a chronically inflamed microenvironment, evade immune recognition, and suppress immune reactivity. Genetic and molecular definition of these three immune hallmarks of cancer offers the opportunity to learn how to deploy specific countermeasures to reverse the situation in favor of the immune system and, eventually, the patient. This new information could be channeled to address what seem to be the three major hallmarks for the immune control of cancer progression: effective procedures to activate immune reactivity; characterization of not-disposable oncoantigens; and counteraction of immune suppression

An integrated approach of immunogenomics and bioinformatics to identify new Tumor Associated Antigens (TAA) for mammary cancer immunological prevention

BACKGROUND: Neoplastic transformation is a multistep process in which distinct gene products of specific cell regulatory pathways are involved at each stage. Identification of overexpressed genes provides an unprecedented opportunity to address the immune system against antigens typical of defined stages of neoplastic transformation. HER-2/neu/ERBB2 (Her2) oncogene is a prototype of deregulated oncogenic protein kinase membrane receptors. Mice transgenic for rat Her2 (BALB-neuT mice) were studied to evaluate the stage in which vaccines can prevent the onset of Her2 driven mammary carcinomas. As Her2 is not overexpressed in all mammary carcinomas, definition of an additional set of tumor associated antigens (TAAs) expressed at defined stages by most breast carcinomas would allow a broader coverage of vaccination. To address this question, a meta-analysis was performed on two transcription profile studies [1,2] to identify a set of new TAA targets to be used instead of or in conjunction with Her2. RESULTS: The five TAAs identified (Tes, Rcn2, Rnf4, Cradd, Galnt3) are those whose expression is linearly related to the tumor mass increase in BALB-neuT mammary glands. Moreover, they have a low expression in normal tissues and are generally expressed in human breast tumors, though at a lower level than Her2. CONCLUSION: Although the number of putative TAAs identified is limited, this pilot study suggests that meta-analysis of expression profiles produces results that could assist in the designing of pre-clinical immunopreventive vaccines

CCL16/LEC powerfully triggers effector and antigen-presenting functions of macrophages and enhances T cell cytotoxicity

AbstractThe huan CC chemokine CCL16, a liver-expressed chemokine, enhances the killing activity of mouse peritoneal macrophages by triggering their expression of tumor necrosis factor α (TNF-α) and Fas ligand. Macrophages also respond to CCL16 by enhancing their production of monocyte chemoattractant protein-1, regulated on activation, normal T cells expressed and secreted chemokines, and interleukin (IL)-1β, TNF-α, and IL-12. The effect of CCL16 is almost as strong as that of lipopolysaccharide and interferon-γ, two of the best macrophage activators. Moreover, CCL16-activated macrophages overexpress membrane CD80, CD86, and CD40 costimulatory molecules and extensively phagocytose tumor cell debris. On exposure to such debris, they activate a strong, tumor-specific, cytolytic response in virgin T cells. Furthermore, cytolytic T cells generated in the presence of CCL16 display a higher cytotoxicity and activate caspase-8 in tumor target cells. This ability to activate caspase-8 depends on their overexpression of TNF-α and Fas ligand induced by CCL16. These data reveal a new function for CCL16 in the immune-response scenario. CCL16 significantly enhances the effector and the antigen-presenting function of macrophages and augments T cell lytic activity

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

There is an ever increasing amount of evidence to support the hypothesis that complement C1q, the first component of the classical complement pathway, is involved in the regulation of cancer growth, in addition to its role in fighting infections. It has been demonstrated that C1q is expressed in the microenvironment of various types of human tumors, including breast adenocarcinomas. This study compares carcinogenesis progression in C1q deficient (neuT-C1KO) and C1q competent neuT mice in order to investigate the role of C1q in mammary carcinogenesis. Significantly accelerated autochthonous neu(+) carcinoma progression was paralleled by accelerated spontaneous lung metastases occurrence in C1q deficient mice. Surprisingly, this effect was not caused by differences in the tumor-infiltrating cells or in the activation of the complement classical pathway, since neuT-C1KO mice did not display a reduction in C3 fragment deposition at the tumor site. By contrast, a significant higher number of intratumor blood vessels and a decrease in the activation of the tumor suppressor WW domain containing oxidoreductase (WWOX) were observed in tumors from neuT-C1KO as compare with neuT mice. In parallel, an increase in Her2/neu expression was observed on the membrane of tumor cells. Taken together, our findings suggest that C1q plays a direct role both on halting tumor angiogenesis and on inducing apoptosis in mammary cancer cells by coordinating the signal transduction pathways linked to WWOX and, furthermore, highlight the role of C1q in mammary tumor immune surveillance regardless of complement system activation