Chemotherapy induced immunogenic cell death alters response to exogenous activation of STING pathway and PD-L1 immune checkpoint blockade in a syngeneic murine model of ovarian cancer

Nersesian, Sarah; Shakfa, Noor; Peterson, Nichole; Vidotto, Thiago; Afriyie-Asante, Afrakoma; Lightbody, Elizabeth D.; Koti, Madhuri

doi:10.1101/824094

Cited by 1 publication

(1 citation statement)

References 40 publications

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“…1E and Supplementary Fig. S1C), which are well-established cytokines involved in ICD [30][31][32][33] . These results show that T-DM1-induced mitotic arrest and apoptosis are accompanied by increased eIF2α phosphorylation, induction of DAMPs and cytokines, indicative of ICD induction.…”

Section: T-dm1 Induces Icd Markers In T-dm1 Sensitive Breast Cancer C...mentioning

confidence: 99%

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

Gedik,

Saatci,

Oberholtzer

et al. 2023

Preprint

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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.

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Section: T-dm1 Induces Icd Markers In T-dm1 Sensitive Breast Cancer C...mentioning

confidence: 99%

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

Gedik,

Saatci,

Oberholtzer

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Chemotherapy induced immunogenic cell death alters response to exogenous activation of STING pathway and PD-L1 immune checkpoint blockade in a syngeneic murine model of ovarian cancer

Cited by 1 publication

References 40 publications

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

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

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