Reviving immunogenic cell death upon targeting TACC3 enhances T-DM1 response in HER2-positive breast cancer

Abstract Immunogenic cell death (ICD), an immune-priming form of cell death, has been shown to be induced by several different anti-cancer therapies. Despite being the first and one of the most successful antibody-drug conjugates (ADCs) approved for refractory HER2-positive breast cancer, little is known if response and resistance to trastuzumab emtansine (T-DM1) involves ICD modulation that can be leveraged to enhance T-DM1 response. Here, we report that T-DM1 induces spindle assembly checkpoint (SAC)-dependent ICD in sensitive cells by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which are lost in resistance. Accordingly, an ICD-related gene signature correlates with clinical response to T-DM1-containing therapy. We found that transforming acidic coiled-coil containing 3 (TACC3) is overexpressed in T-DM1 resistant cells, and that T-DM1 responsive patients have reduced TACC3 protein while the non-responders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacological inhibition of TACC3 revives T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition elicits ICD in vivo shown by vaccination assay, and it potentiates T-DM1 by inducing dendritic cell (DC) maturation and enhancing infiltration of cytotoxic T cells in the human HER2-overexpressing MMTV.f.huHER2#5 (Fo5) transgenic model. Together, our results show that ICD is a key mechanism of action of T-DM1 which is lost in resistance, and that targeting TACC3 restores T-DM1-mediated ICD and overcomes resistance.Statement of Significance Immunogenic cell death (ICD) is a novel mechanism of T-DM1 cytotoxicity that is lost upon T-DM1 resistance. Targeting TACC3 reinstates T-DM1-induced ICD, thus representing an attractive strategy to overcome T-DM1 resistance..

Medienart:	Preprint

Erscheinungsjahr:	2023
Erschienen:	2023

Enthalten in:	bioRxiv.org - (2023) vom: 19. Sept. Zur Gesamtaufnahme - year:2023

Sprache:	Englisch

Beteiligte Personen:

Gedik, Mustafa Emre [VerfasserIn] Saatci, Ozge [VerfasserIn] Oberholtzer, Nathaniel [VerfasserIn] Uner, Meral [VerfasserIn] Akbulut, Ozge [VerfasserIn] Cetin, Metin [VerfasserIn] Aras, Mertkaya [VerfasserIn] Ibis, Kubra [VerfasserIn] Caliskan, Burcu [VerfasserIn] Banoglu, Erden [VerfasserIn] Wiemann, Stefan [VerfasserIn] Uner, Aysegul [VerfasserIn] Aksoy, Sercan [VerfasserIn] Mehrotra, Shikhar [VerfasserIn] Sahin, Ozgur [VerfasserIn]

Links:	Volltext [kostenfrei]

Themen:	570 Biology

doi:	10.1101/2023.09.12.557273

funding:
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PPN (Katalog-ID):	XBI040852768