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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2024 | Breast Cancer | Research

NK cell-triggered CCL5/IFNγ-CXCL9/10 axis underlies the clinical efficacy of neoadjuvant anti-HER2 antibodies in breast cancer

Authors: Sara Santana-Hernández, Jesús Suarez-Olmos, Sonia Servitja, Pau Berenguer-Molins, Marcel Costa-Garcia, Laura Comerma, Anna Rea, Julia Perera-Bel, Silvia Menendez, Oriol Arpí, Begoña Bermejo, María Teresa Martínez, Juan Miguel Cejalvo, Iñaki Comino-Méndez, Javier Pascual, Emilio Alba, Miguel López-Botet, Federico Rojo, Ana Rovira, Joan Albanell, Aura Muntasell

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

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.

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Title: NK cell-triggered CCL5/IFNγ-CXCL9/10 axis underlies the clinical efficacy of neoadjuvant anti-HER2 antibodies in breast cancer
Authors: Sara Santana-Hernández
Jesús Suarez-Olmos
Sonia Servitja
Pau Berenguer-Molins
Marcel Costa-Garcia
Laura Comerma
Anna Rea
Julia Perera-Bel
Silvia Menendez
Oriol Arpí
Begoña Bermejo
María Teresa Martínez
Juan Miguel Cejalvo
Iñaki Comino-Méndez
Javier Pascual
Emilio Alba
Miguel López-Botet
Federico Rojo
Ana Rovira
Joan Albanell
Aura Muntasell
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Breast Cancer
Breast Cancer
Trastuzumab
Biomarkers
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-023-02918-4

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