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

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,Muntasell AuraORCID

Abstract

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.

Funder

Instituto de Salud Carlos III

Agència de Gestió d'Ajuts Universitaris i de Recerca

Fundación Científica Asociación Española Contra el Cáncer

Ministerio de Ciencia e Innovación

H2020 Marie Skłodowska-Curie Actions

Publisher

Springer Science and Business Media LLC

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1. Hodgkin lymphoma and liquid biopsy: a story to be told;Journal of Experimental & Clinical Cancer Research;2024-07-02

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