Immune Checkpoint Profiles in Luminal B Breast Cancer (Alliance)
A partir de l'analyse de données moléculaires issues d'un essai évaluant un inhibiteur d'aromatase en traitement néoadjuvant chez des patientes atteintes d'un cancer du sein, cette étude met en évidence la surexpression, dans les tumeurs de type luminal B résistantes aux inhibiteurs d'aromatase, de gènes pouvant constituer des cibles thérapeutiques pour des inhibiteurs de points de contrôle immunitaire
Background : Unlike estrogen receptor (ER) negative breast cancer, ER-positive breast cancer outcome is less influenced by lymphocyte content indicating the presence of immune tolerance mechanisms that may be specific to this disease subset. Methods : A supervised analysis of microarray data from the Alliance/ACOSOG Z1031 neoadjuvant aromatase inhibitor (AI) trial identified upregulated genes in Luminal B breast cancers that correlated with AI-resistant tumor proliferation (Pearson’s correlation r ≥ 0.4 with Ki67) (33 cases Ki67 >10% on AI) versus Luminal-B breast cancers that were more AI-sensitive (33 cases Ki67 <10% on AI). Over-representation analysis was performed using Webgestalt. Results : Thirty candidate genes positively correlated (r ≥ 0.4) with AI-resistant proliferation in Luminal B and were upregulated >2 fold. Gene ontologies identified that the targetable immune-checkpoint components IDO1, LAG3, and PD1 were over-represented resistance candidates (p ≤ 0.001). High IDO1 mRNA associated with poor prognosis in luminal-B disease (METABRIC, HR = 1.43, CI 1.04 − 1.98, p = 0.03). IDO1 also statistically significantly correlated with STAT1 at protein level in luminal-B disease (Pearson’s r = 0.74). As a composite immune tolerance signature, expression of IFN-
γ/STAT1 pathway components associated with higher baseline Ki67, lower estrogen and progesterone receptor mRNA levels and worse disease specific survival (p
= 0.002). In a tissue microarray analysis (TMA), IDO1 was observed in stromal cells and tumor-associated macrophages, with a higher incidence in Luminal-B cases. Furthermore, IDO1 expression associated with a macrophage mRNA signature (M1 by CIBERSORT Pearson’s r = 0.62 ) and also by TMA analysis. Conclusion : Targetable immune-checkpoint components are upregulated in majority of endocrine therapy resistant Luminal-B cases. Our findings provide rationale for immune checkpoint inhibition in poor outcome ER+ breast cancer.