A multivariate Th17 metagene for prognostic stratification in T cell non-inflamed triple negative breast cancer

L Faucheux; M Grandclaudon; M Perrot-Dockès; P Sirven; F Berger; A S Hamy; V Fourchotte; A Vincent-Salomon; F Mechta-Grigoriou; F Reyal; A Scholer-Dahirel; M Guillot-Delost; V Soumelis

doi:10.1080/2162402X.2019.1624130

A multivariate Th17 metagene for prognostic stratification in T cell non-inflamed triple negative breast cancer

Oncoimmunology. 2019 Jun 24;8(9):e1624130. doi: 10.1080/2162402X.2019.1624130. eCollection 2019.

Authors

L Faucheux^{1

2}, M Grandclaudon^{1

2}, M Perrot-Dockès^{1

2}, P Sirven^{1

3}, F Berger^{1

4}, A S Hamy^{1

5}, V Fourchotte⁶, A Vincent-Salomon^{7

8}, F Mechta-Grigoriou^{1

3}, F Reyal^{1

5

6}, A Scholer-Dahirel^{1

3}, M Guillot-Delost^{1

2

9}, V Soumelis^{1

2

9}

Affiliations

¹ Institut Curie, PSL Research University, Paris, France.
² Immunity and Cancer, Integrative Biology of Human Dendritic Cells and T Cells Laboratory, UMR 932 Immunity and Cancer, INSERM, Paris, France.
³ Stress and cancer laboratory, U830 Genetics and Biology of cancers, INSERM, Paris, France.
⁴ U900, Unit of biometry, INSERM, Paris, France.
⁵ Departement of translational research, Residual tumor and response to treatment laboratory (RT2Lab), UMR 932 Immunity and Cancer, INSERM, Paris, France.
⁶ Departement of Surgical Oncology, Institut Curie, Paris, France.
⁷ Diagnostic and Theranostic medicine division, Institut Curie, Paris, France.
⁸ Department of Biopathology, U934, INSERM, Paris, France.
⁹ Center of Clinical Investigation, CIC IGR-Curie 1428, Paris, France.

Abstract

A diversity of T helper (Th) subsets (Th1, Th2, Th17) has been identified in the human tumor microenvironment. In breast cancer, the role of Th subsets remains controversial, and a systematic study integrating Th subset diversity, T cell inflammation, breast cancer molecular subtypes, and patient prognosis, is lacking. In primary untreated breast cancer samples, we analyzed 19 Th cytokines at the protein level. Eight were T cell-specific, and subsequently measured in 106 prospectively-collected untreated samples. The dominant Th cytokines across all breast cancer samples were IFN-γ and IL-2. Th2 cytokines (IL-4, IL-5, IL-13) were expressed at low levels and not associated with any breast cancer subtype. Th17 cytokines (IL-17A and IL-17F) were up-regulated in triple negative breast cancer (TNBC), specifically in T cell non-inflamed tumors. In order to get insight into prognosis, we exploited the METABRIC transcriptomic dataset. We derived Th1, Th2, and Th17 metagenes based on manually curated Th signatures, and found that a high Th17 metagene was of good prognosis in T cell non-inflamed TNBC. Multivariate Cox modeling selected the Nottingham Prognostic Index (NPI), Th2 and Th17 metagenes as additive predictors of breast cancer-specific survival, which defined novel and highly distinct prognostic groups within TNBC. Our results reveal that Th17 is a novel prognostic composite biomarker in T cell non-inflamed TNBC. Integrating immune cell and tumor molecular diversity is an efficient strategy for prognostic stratification of cancer patients.

Keywords: Breast cancer; T cells; Th17; prognostic stratification; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

Grants and funding

This work was supported by the Institut National de la Santé et de la Recherche Médicale under Grants BIO2012-02, BIO2014-08, and HTE2016; Agence Nationale de la Recherche under Grants ANR-10-IDEX-0001-02 PSL*, ANR-11-LABX-0043, ANR-13-BSV1-0024-02 and ANR-16-CE15-0024-01; European Research Council under Grant IT-DC 281987; Institut National du Cancer under Grant EMERG-15-ICR-1; Fondation ARC pour la Recherche sur le Cancer under Grants PJA 20131200436, and DOC20160604230 to M.G.; Agence Nationale de Recherches sur le Sida et les hépatites virales to M.G.; Fondation pour la Recherche Médicale to M. G; Ligue nationale contre le cancer (labelization EL2016.LNCC/VaS); and Institut Curie, in particular the PIC TME .