Fondation MEDIC

www.fondation-medic.ch

Exploring the immune infiltrate in human breast cancer
[24.10.2016]
Project leader – Karen Willard-Gallo
Karen Willard-Gallo

Karen Willard-Gallo, Ph.D. is head of the Molecular Immunology Laboratory at the Institut Jules Bordet (Université Libre de Bruxelles), a research team of basic and translational research scientists and clinicians investigating lymphocyte abnormalities in cancer. She performed her thesis research in Immunology and Molecular Biology at Argonne National Laboratory, University of Chicago in partnership with Virginia Polytechnic Institute. Arriving in Belgium for a post-doc at the Ludwig Institute for Cancer Research in Brussels she remained at the Université Catholique de Louvain for several years as an Associate Member of the de Duve Institute where her studies focused on mechanisms that regulate gene expression in normal and abnormal human CD4+ T cells. In 1994, she moved her research activities to the Université Libre de Bruxelles, first in the Department of Molecular Biology and five years later to the Institut Jules Bordet to facilitate her research on human cancer. She is currently head of the Molecular Immunology Laboratory at Bordet where her basic and translational research interests focus on understanding mechanisms regulating anti-tumor immune responses in breast cancer.

Institut Jules Bordet, Université Libre de Bruxelles
127 Boulevard de Waterloo
(Wing L)
1000 Bruxelles, Belgium

E-mail: karen.willard-gallo@bordet.be or kwillard@ulb.ac.be
Phone: +32-2-541-3739

Group members
 

Soizic Garaud, PhD

Immunologist

Grégory Noël, PhD

Immunologist

Gert Van den Eynden, MD

Pathologist at GZA

Laurence Buisseret, MD

Doctoral thesis student (collaborative with BCTL)

Cinzia Solinas, MD

Medical Oncologist, Doctoral thesis student

Mireille Langouo Fontsa, MD

Doctoral thesis student

Edoardo Migliori, MS

Doctoral thesis student

Pushpamali De Silva, MS

Doctoral thesis student

Sylvia Pecenko, MS

Doctoral thesis student

Anaïs Boisson, MS

Laboratory Associate

Hugues Duvillier, MS

Cytometrist

Celine Naveaux

Laboratory Technician

Laurence Van Schoonwinkel

Laboratory Technician

Hélène Strainchamps

administrative assistant

Project description
 

This project explores the nature of the immune infiltrate in human breast cancer (BC) with the goal of identifying critical compositional and organizational differences related to clinical outcomes. Our previous work found that organized tertiary lymphoid structures (TLS; see Figure), forming in the peri-tumoral stroma of BC, are characterized by the specific presence of CD4+ follicular helper T (Tfh) cells and CXCL13 expression, both predictive for positive outcomes (Gu-Trantien et al. 2013 J. Clin. Invest). Our recent prospective study of fresh BC tissues shows that the extent of tumor infiltrating lymphocytes (TIL) within our cohort forms a continuum (see Figure; Buisseret et al., in revision for Oncoimmunol.), a curve that is maintained irrespective of patient numbers (current cohort n>725 patients). We further find that important compositional differences, which are not linked to the extent of tumor infiltration alone, are clinically relevant (Gu-Trantien et al., manuscript in preparation).

figure 1

Our current work involves both prospective studies to understand the functionality of specific TIL subpopulations and how they organize into TLS as well as retrospective studies that seek to apply these findings to a grading system that scores an individual patient’s anti-tumor immune response for use in BC treatment decisions (immunological grade). The Molecular Immunology laboratory is investigating the following specific questions:

  • What is the prognostic and predictive value of detecting TIL and TLS in BC?
  • Are their compositional differences in TIL and TLS that are associated with differences in clinical outcome?
  • What are the molecular mediators that regulate CD4+ T and B cell infiltration in BC?
  • What are the roles that specific specific subsets of CD4+ T and B cell TILs play in anti-tumor immune responses and clinical outcome?
  • How does aberrant expression of the transcription factor FOXP1 play a role in CD4+ T cell persistence and expansion and is this linked with anti-tumor immunity?
  • Are their links between anti-tumor immune responses and specific mutations in triple negative BC? In HER2+ BC?
  • What are the clinically relevant immune checkpoint molecules expressed in BC?
  • Can we implement an immunological grade for BC that helps to guide treatment decisions for conventional chemotherapy, radiotherapy and/or new immunotherapies?

Ultimately, our goal is to further understand how we the power and the specificity of the immune response can be harnessed to produce effective and sustained anti-tumor immunity.

Publications
 
2016 / 10.1038/modpathol.2016.109
Denkert C, Wienert S, Poterie A, Loibl S, Budczies J, Badve S, Bago-Horvath Z, Bane A, Bedri S, Brock J, Chmielik E, Christgen M, Colpaert C, Demaria S, Van den Eynden G, Floris G, Fox SB, Gao D, Ingold Heppner B, Kim SR, Kos Z, Kreipe HH, Lakhani SR, Penault-Llorca F, Pruneri G, Radosevic-Robin N, Rimm DL, Schnitt SJ, Sinn BV, Sinn P, Sirtaine N, O'Toole SA, Viale G, Van de Vijver K, de Wind R, von Minckwitz G, Klauschen F, Untch M, Fasching PA, Reimer T, Willard-Gallo K, Michiels S, Loi S, Salgado R. Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group. Mod Pathol. 2016 Oct;29(10):1155-64
» PubMed
2016 / 10.1039/c5an01512j
Verdonck M, Denayer A, Delvaux B, Garaud S, De Wind R, Desmedt C, Sotiriou C, Willard-Gallo K, Goormaghtigh E. Characterization of human breast cancer tissues by infrared imaging. Analyst. 2016 Jan 21;141(2):606-19
» PubMed
2015 / 10.1016/j.celrep.2015.09.032
Fumagalli D, Gacquer D, Rothé F, Lefort A, Libert F, Brown D, Kheddoumi N, Shlien A, Konopka T, Salgado R, Larsimont D, Polyak K, Willard-Gallo K, Desmedt C, Piccart M, Abramowicz M, Campbell PJ, Sotiriou C, Detours V. Principles Governing A-to-I RNA Editing in the Breast Cancer Transcriptome. Cell Rep. 2015 Oct 13;13(2):277-89
» PubMed
2015 / 10.1093/annonc/mdu450
Salgado R*, Denkert C*, Demaria S*, Sirtaine N, Klauschen F, Pruneri G, Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F, Perez EA, Thompson EA, Symmans WF, Richardson AL, Brock J, Criscitiello C, Bailey H, Ignatiadis M, Floris G, Sparano J, Kos Z, Nielsen T, Rimm DL, Allison KH, Reis-Filho JS, Loibl S, Sotiriou C, Viale G, Badve S, Adams S*, Willard-Gallo K* and Loi S* (*contributed equally). The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015 Feb;26(2):259-71
» PubMed
2015 / 10.1007/s12609-014-0178-4
Dushyanthan S, Savas P, Willard-Gallo K, Denkert C, Salgado R, Loi S.. Tumor infiltrating lymphocytes (TILs) in breast cancer. Curr. Breast Cancer Rep. 7: 59
» PubMed
2015 / 10.1038/icb.2015.39
Garaud S, Willard-Gallo K. IRF5: a rheostat for tumor-infiltrating lymphocyte trafficking in breast cancer?. Immunol Cell Biol. 2015 May-Jun;93(5):425-6
» PubMed
2015 / 10.1039/c4an01855a
Verdonck M, Garaud S, Duvillier H, Willard-Gallo K, Goormaghtigh E. Label-free phenotyping of peripheral blood lymphocytes by infrared imaging. Analyst. 2015 Apr 7;140(7):2247-56
» PubMed
2014 / 10.3791/52392
Garaud S, Gu-Trantien C, Lodewyckx JN, Boisson A, De Silva P, Buisseret L, Migliori E, Libin M, Naveaux C, Duvillier H, Willard-Gallo K. A simple and rapid protocol to non-enzymatically dissociate fresh human tissues for the analysis of infiltrating lymphocytes. J Vis Exp. 2014 Dec 6;(94)
» PubMed
2013 / 10.1172/JCI67428
Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A, Ravoet M, Le Buanec H, Sibille C, Manfouo-Foutsop G, Veys I, Haibe-Kains B, Singhal SK, Michiels S, Rothé F, Salgado R, Duvillier H, Ignatiadis M, Desmedt C, Bron D, Larsimont D, Piccart M, Sotiriou C, Willard-Gallo K. CD4⁺ follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013 Jul;123(7):2873-92
» PubMed