Anti-idiotype and anti-immunoglobulin antibodies are promising biomarkers of early breast cancer

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1 Anti-idiotype and anti-immunoglobulin antibodies are promising biomarkers of early breast cancer Marie-Claire Maroun, Lawrence Grossman, Rooshan Arshad, Leonard Lipovich, and Félix Fernández Madrid Wayne State University, Detroit, Michigan, USA

2 Disclosures None Supported by NIH R01 CA

3 Just a glimpse Towards a network theory of the immune system 1974

4 Some Grammar in Immunology!

5 The Idiotype Network Theory Kieber-Emmons et al. Frontiers in oncology. 2012

6 Ab2 is a surrogate of Ag

7 Anti-idiotypic antibodies in autoimmune diseases

8 Background data IFA pattern [%]* Convenien ce control Female Osteoarthr itis control Female Benign breast disease Ductal carcinoma in situ Invasive carcinoma Homogeneous Speckled Anti-nucleolar Anti-centromere Anti-centrosome Antimitochondrial Multiple nuclear dots Cytoskeletal Mixed pattern Other

9 Background data IFA pattern [%]* Convenien ce control Female Osteoarthr itis control Female Benign breast disease Ductal carcinoma in situ Invasive carcinoma Homogeneous Speckled Anti-nucleolar Anti-centromere Anti-centrosome Antimitochondrial Multiple nuclear dots Cytoskeletal Mixed pattern Other

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11 Significance of autoantibodies in BC Antigens: a plethora of BC tumor-associated antigens [TAAs] Expression of a B-cell and T-cell-orchestrated anti-cancer immune response Potential diagnostic and prognostic biomarkers of BC Identification of molecular targets involved in carcinogenesis

12 Objectives Characterize and identify the specificity of the autoantibodies detected by immunofluorescence To assess the relative contribution of cancer cells versus cancer tissue

13 Methods Immunoscreening of 2 cdna libraries of breast cancer autoantigens with BC sera mrna from invasive BC tissue mrna from isolated 8 BC cell lines Autoantigen microarray Sequence analyses and homology searches

14 Results Cloning of autoantibodies recognizing multiple idiotypes and allotypes of immunoglobulins

15 Results Cloning of autoantibodies recognizing multiple idiotypes and allotypes of immunoglobulins Targets: IgG1 constant and variable region Lambda light chain variable region Heavy chain constant and variable region

16 Results Cloning of autoantibodies recognizing multiple idiotypes and allotypes of immunoglobulins Targets: IgG1 constant and variable region Lambda light chain variable region Heavy chain constant and variable region No anti-idiotype immunoglobulins were cloned by immunoscreening the cdna library from established BC cell lines

17 Idiotypes identified (anti-anti-v region of IgG1) Protein Function TNF-alpha IL-13 IL-17a Peptide/ MHC complex HLA-A1 TARP HEDGEHOG ERBB2 NOTCH EGFR VEGF CD18 Collagen VII Pro-Inflammatory cytokine Pro-Inflammatory cytokine Pro-Inflammatory cytokine Immune surveillance TSA Signaling pathway Signaling pathway Signaling pathway Receptor-signaling pathway Cytokine-Angiogenic Integrin-cell adhesion-cell surface signaling Basement membrane-tumor Invasion

18 Idiotypes identified (anti-anti-v region of IgG1) Protein Function TNF-alpha IL-13 IL-17a Peptide/ MHC complex HLA-A1 TARP HEDGEHOG ERBB2 NOTCH EGFR VEGF CD18 Collagen VII Pro-Inflammatory cytokine Pro-Inflammatory cytokine Pro-Inflammatory cytokine Immune surveillance TSA Signaling pathway Signaling pathway Signaling pathway Receptor-signaling pathway Cytokine-Angiogenic Integrin-cell adhesion-cell surface signaling Basement membrane-tumor Invasion

19 Idiotypes identified (anti-anti-v region of IgG1) Protein Function TNF-alpha IL-13 IL-17a Peptide/ MHC complex HLA-A1 TARP HEDGEHOG ERBB2 NOTCH EGFR VEGF CD18 Collagen VII Pro-Inflammatory cytokine Pro-Inflammatory cytokine Pro-Inflammatory cytokine Immune surveillance TSA Signaling pathway Signaling pathway Signaling pathway Receptor-signaling pathway Cytokine-Angiogenic Integrin-cell adhesion-cell surface signaling Basement membrane-tumor Invasion

20 Conclusions Antigen-driven anti-autoantibody synthesis and maturation takes place in breast tumor tissue Antibodies, when performing the function of autoantigens, elicit an idiotypic response that could be a marker of cancer Idiotypes identifed may be involved in cancer pathogenesis

21 Conclusions Autoimmunity driven by TAAs Inflammation Breast carcinogenesis

22 What s next? Panel of biomarkers for early breast cancer Targeted therapy in breast cancer

23 Acknowledgements Collaborators Lawrence Grossman Rooshan Arshad Leonard Lipovich Michael Long Azadeh Stark Carol L. Peebles Félix Fernández Madrid Participating institutions Wayne State University Karmanos Cancer Institute, Detroit, MI INOVA, San Diego, CA Geisinger Health System, Danville, PA Henry Ford Health System, Detroit, MI