The cellular ratio of immune tolerance (immunoCRIT) is a definite marker for aggressiveness of solid tumors and may explain tumor dissemination patterns.
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.
Epiontis GmbH; Berlin, Germany.
Ivana
I
Türbachova
Epiontis GmbH; Berlin, Germany.
Tim
T
Schwachula
Epiontis GmbH; Berlin, Germany.
Ines
I
Vasconcelos
Clinics for Obstetrics and Gynecology; University Greifswald; Greifswald, Germany.
Alexander
A
Mustea
Epiontis GmbH; Berlin, Germany.
Tina
T
Baldinger
Regulatory Biology Laboratory; The Salk Institute for Biological Studies; La Jolla, CA USA.
Katherine A
KA
Jones
Zentrum für Molekulare Biologie Heidelberg; INF 282; University Heidelberg; Heidelberg, Germany.
Hermann
H
Bujard
Nobel Education; Schönau am Königssee, Germany.
Alexander
A
Olek
Labor für Abstammungsbegutachtung; Prague, Czech Republic.
Klaus
K
Olek
Epiontis GmbH; Berlin, Germany.
Katharina
K
Gellhaus
Clinics for Obstetrics and Gynecology; University Medicine Charité Campus Virchow; Berlin, Germany.
Ioana
I
Braicu
Clinics for Obstetrics and Gynecology; University Greifswald; Greifswald, Germany.
Dominique
D
Könsgen
Novartis; Cambridge, MA USA.
Christy
C
Fryer
Saatchi & Saatchi Health; Milan, Italy.
Elisabetta
E
Ravot
Epiontis GmbH; Berlin, Germany.
Alexander
A
Hellwag
IDEXX Laboratories; Basel, Switzerland.
Nicole
N
Westerfeld
DKFZ-ZMBH Allianz; Zentrum für Molekulare Biologie Heidelberg; University Heidelberg; Heidelberg, Germany.
Oliver J
OJ
Gruss
Division of Infection and Immunity; Institute of Biomedical Life Sciences; Wellcome Centre for Molecular Parasitology; Glasgow Biomedical Research Centre; University of Glasgow; Glasgow, UK.
Markus
M
Meissner
Department of Molecular Neurobiology; Max Planck Institute for Medical Research; Heidelberg, Germany.
Mazahir T
MT
Hasan
Epiontis GmbH; Berlin, Germany.
Michael
M
Weber
Epiontis GmbH; Berlin, Germany.
Ulrich
U
Hoffmüller
Epiontis GmbH; Berlin, Germany.
Sven
S
Zimmermann
PATHOTRES Gemeinschaftspraxis für Pathologie und Neuropathologie; Berlin, Germany.
Christoph
C
Loddenkemper
Department of Gynecology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany.
Sven
S
Mahner
Nephrologie und internistische Intensivmedizin; Charité Universitätsmedizin Berlin Campus Virchow; Berlin, Germany.
Nina
N
Babel
Erasmus University Medical Center- Daniel den Hoed Cancer Center Dept Medical Oncology; Rotterdam, The Netherlands.
Els
E
Berns
School of Medicine; Cardiff University; Cardiff, UK.
Richard
R
Adams
Molecular Oncology Group; Medical University of Vienna; Vienna, Austria.
Robert
R
Zeilinger
Epiontis GmbH; Berlin, Germany.
Udo
U
Baron
Department of Obstetrics and Gynecology; University of Leuven; Leuven, Belgium.
Ignace
I
Vergote
Gray Institute for Radiation Oncology and Biology; University of Oxford; Oxford, UK.
Tim
T
Maughan
Department of Gynecology; University of Heidelberg; Heidelberg, Germany.
Frederik
F
Marme
Department of Mathematics; Humboldt University; Berlin, Germany.
Thorsten
T
Dickhaus
Clinics for Obstetrics and Gynecology; University Medicine Charité Campus Virchow; Berlin, Germany.
Jalid
J
Sehouli
Epiontis GmbH; Berlin, Germany.
Sven
S
Olek
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D055815:Young Adult
D014408:Biomarkers, Tumor
T lymphocytes; epigenetic immunophenotyping; immunoCRIT; ovarian cancer; regulatory T cells; tumor immunology; tumor metastasis