학술논문
NK cell-triggered CCL5/IFNγ-CXCL9/10 axis underlies the clinical efficacy of neoadjuvant anti-HER2 antibodies in breast cancer.
Document Type
Article
Author
Santana-Hernández, Sara; Suarez-Olmos, Jesús; Servitja, Sonia; Berenguer-Molins, Pau; Costa-Garcia, Marcel; Comerma, Laura; Rea, Anna; Perera-Bel, Julia; Menendez, Silvia; Arpí, Oriol; Bermejo, Begoña; Martínez, María Teresa; Cejalvo, Juan Miguel; Comino-Méndez, Iñaki; Pascual, Javier; Alba, Emilio; López-Botet, Miguel; Rojo, Federico; Rovira, Ana; Albanell, Joan
Source
Subject
*KILLER cells
*HER2 positive breast cancer
*BREAST cancer
*NEOADJUVANT chemotherapy
*IMMUNOGLOBULINS
*HORMONE receptor positive breast cancer
*RECTAL cancer
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Language
ISSN
1756-9966
Abstract
Background: The variability in responses to neoadjuvant treatment with anti-HER2 antibodies prompts to personalized clinical management and the development of innovative treatment strategies. Tumor-infiltrating Natural Killer (TI-NK) cells can predict the efficacy of HER2-targeted antibodies independently from clinicopathological factors in primary HER2-positive breast cancer patients. Understanding the mechanism/s underlying this association would contribute to optimizing patient stratification and provide the rationale for combinatorial approaches with immunotherapy. Methods: We sought to uncover processes enriched in NK cell-infiltrated tumors as compared to NK cell-desert tumors by microarray analysis. Findings were validated in clinical trial-derived transcriptomic data. In vitro and in vivo preclinical models were used for mechanistic studies. Findings were analysed in clinical samples (tumor and serum) from breast cancer patients. Results: NK cell-infiltrated tumors were enriched in CCL5/IFNG-CXCL9/10 transcripts. In multivariate logistic regression analysis, IFNG levels underlie the association between TI-NK cells and pathological complete response to neoadjuvant treatment with trastuzumab. Mechanistically, the production of IFN-ɣ by CD16+ NK cells triggered the secretion of CXCL9/10 from cancer cells. This effect was associated to tumor growth control and the conversion of CD16 into CD16-CD103+ NK cells in humanized in vivo models. In human breast tumors, the CD16 and CD103 markers identified lineage-related NK cell subpopulations capable of producing CCL5 and IFN-ɣ, which correlated with tissue-resident CD8+ T cells. Finally, an early increase in serum CCL5/CXCL9 levels identified patients with NK cell-rich tumors showing good responses to anti-HER2 antibody-based neoadjuvant treatment. Conclusions: This study identifies specialized NK cell subsets as the source of IFN-ɣ influencing the clinical efficacy of anti-HER2 antibodies. It also reveals the potential of serum CCL5/CXCL9 as biomarkers for identifying patients with NK cell-rich tumors and favorable responses to anti-HER2 antibody-based neoadjuvant treatment. [ABSTRACT FROM AUTHOR]