The adaptive immune system is involved in tumor establishment and aggressiveness. Tumors of the ovaries, an immune-privileged organ, spread via transceolomic routes and rarely to distant organs. This is contrary to tumors of non-immune privileged organs, which often disseminate hematogenously to distant organs. Epigenetics-based immune cell quantification allows direct comparison of the immune status in benign and malignant tissues and in blood. Here, we introduce the "cellular ratio of immune tolerance" (immunoCRIT) as defined by the ratio of regulatory T cells to total T lymphocytes. The immunoCRIT was analyzed on 273 benign tissue samples of colorectal, bronchial, renal and ovarian origin as well as in 808 samples from primary colorectal, bronchial, mammary and ovarian cancers. ImmunoCRIT is strongly increased in all cancerous tissues and gradually augmented strictly dependent on tumor aggressiveness. In peripheral blood of ovarian cancer patients, immunoCRIT incrementally increases from primary diagnosis to disease recurrence, at which distant metastases frequently occur. We postulate that non-pathological immunoCRIT values observed in peripheral blood of immune privileged ovarian tumor patients are sufficient to prevent hematogenous spread at primary diagnosis. Contrarily, non-immune privileged tumors establish high immunoCRIT in an immunological environment equivalent to the bloodstream and thus spread hematogenously to distant organs. In summary, our data suggest that the immunoCRIT is a powerful marker for tumor aggressiveness and disease dissemination.

Clinics for Obstetrics and Gynecology; University Greifswald; Greifswald Germany

Clinics for Obstetrics and Gynecology; University Medicine Charité Campus Virchow; Berlin Germany

Department of Gynecology; University Medical Center Hamburg Eppendorf; Hamburg Germany

Department of Gynecology; University of Heidelberg; Heidelberg Germany

Department of Mathematics; Humboldt University; Berlin Germany

Department of Molecular Neurobiology; Max Planck Institute for Medical Research; Heidelberg Germany

Department of Obstetrics and Gynecology; University of Leuven; Leuven Belgium

Division of Infection and Immunity; Institute of Biomedical Life Sciences; Wellcome Centre for Molecular Parasitology; Glasgow Biomedical Research Centre; University of Glasgow; Glasgow UK

DKFZ ZMBH Allianz; Zentrum für Molekulare Biologie Heidelberg; University Heidelberg; Heidelberg Germany

Epiontis GmbH; Berlin Germany

Erasmus University Medical Center Daniel den Hoed Cancer Center Dept Medical Oncology; Rotterdam The Netherlands

Gray Institute for Radiation Oncology and Biology; University of Oxford; Oxford UK

IDEXX Laboratories; Basel Switzerland

Labor für Abstammungsbegutachtung; Prague Czech Republic

Molecular Oncology Group; Medical University of Vienna; Vienna Austria

Nephrologie und internistische Intensivmedizin; Charité Universitätsmedizin Berlin Campus Virchow; Berlin Germany

Nobel Education; Schönau am Königssee Germany

Novartis; Cambridge MA USA

PATHOTRES Gemeinschaftspraxis für Pathologie und Neuropathologie; Berlin Germany

Regulatory Biology Laboratory; The Salk Institute for Biological Studies; La Jolla CA USA

Saatchi and Saatchi Health; Milan Italy

School of Medicine; Cardiff University; Cardiff UK

Zentrum für Molekulare Biologie Heidelberg; INF 282; University Heidelberg; Heidelberg Germany

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