Targeting TACC3 induces immunogenic cell death and enhances T-DM1 response in HER2-positive breast cancer
Trastuzumab emtansine (T-DM1) was the first and one of the most successful antibody-drug conjugates (ADCs) approved for treating refractory HER2-positive breast cancer. Despite its initial clinical efficacy, resistance is unfortunately common, necessitating approaches to improve response. Here, we found that in sensitive cells T-DM1 induced spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD), an immune-priming form of cell death. The payload of T-DM1 mediated ICD by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which were lost in resistance. Accordingly, ICD-related gene signatures in pre-treatment samples correlated with clinical response to T-DM1-containing therapy, and increased infiltration of anti-tumor CD8+ T cells in post-treatment samples was correlated with better T-DM1 response. Transforming acidic coiled-coil containing 3 (TACC3) was overexpressed in T-DM1 resistant cells, and T-DM1 responsive patients had reduced TACC3 protein expression while non-responders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacological inhibition of TACC3 restored T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition in vivo elicited ICD in a vaccination assay and potentiated the anti-tumor efficacy of T-DM1 by inducing dendritic cell maturation and enhancing intratumoral infiltration of cytotoxic T cells. Together, these results illustrate that ICD is a key mechanism of action of T-DM1 that is lost in resistance and that targeting TACC3 can restore T-DM1-mediated ICD and overcome resistance.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Cancer research - (2024) vom: 06. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gedik, Mustafa Emre [VerfasserIn] |
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Date Revised 22.02.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Sep 14;:. - PMID 37745348 Citation Status Publisher |
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| doi: |
10.1158/0008-5472.CAN-23-2812 |
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NLM368084965 |
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| 520 | |a Trastuzumab emtansine (T-DM1) was the first and one of the most successful antibody-drug conjugates (ADCs) approved for treating refractory HER2-positive breast cancer. Despite its initial clinical efficacy, resistance is unfortunately common, necessitating approaches to improve response. Here, we found that in sensitive cells T-DM1 induced spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD), an immune-priming form of cell death. The payload of T-DM1 mediated ICD by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which were lost in resistance. Accordingly, ICD-related gene signatures in pre-treatment samples correlated with clinical response to T-DM1-containing therapy, and increased infiltration of anti-tumor CD8+ T cells in post-treatment samples was correlated with better T-DM1 response. Transforming acidic coiled-coil containing 3 (TACC3) was overexpressed in T-DM1 resistant cells, and T-DM1 responsive patients had reduced TACC3 protein expression while non-responders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacological inhibition of TACC3 restored T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition in vivo elicited ICD in a vaccination assay and potentiated the anti-tumor efficacy of T-DM1 by inducing dendritic cell maturation and enhancing intratumoral infiltration of cytotoxic T cells. Together, these results illustrate that ICD is a key mechanism of action of T-DM1 that is lost in resistance and that targeting TACC3 can restore T-DM1-mediated ICD and overcome resistance | ||
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