Tumor Immunogenic Cell Death as a Mediator of Intratumor CD8 T-Cell Recruitment

Roussot, Nicolas; Ghiringhelli, François; Rébé, Cédric

doi:10.3390/cells11223672

Cited by 28 publications

(16 citation statements)

References 166 publications

(187 reference statements)

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“…Interestingly, the cytokine that showed the second-largest increase with HSF1 knockdown was CCL5/RANTES (Fig. 7A), which is a canonical chemokine for CD8+ T cells (67). While this array measured secreted protein, the transcript levels of CCL5 from RNA-seq of control and HSF1 knockdown 4T1 cells showed similar increases with knockdown of HSF1, which was confirmed with qPCR in both mouse and human breast cancer cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

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HSF1 excludes CD8+ T cells from breast tumors via suppression of CCL5

Carpenter

Ray

Wang

et al. 2022

Preprint

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Cells have evolved mechanisms for response to external stressors in order to maintain cell viability in the face of changes in the environment. The response to heat stress is driven by the transcription factor heat shock factor 1 (HSF1), which is considered the master regulator of the heat shock response. Here we report a new HSF1 gene signatured termed “HSF1 Activity Signature,” or HAS, which is a 23-gene signature that more specifically assesses HSF1 transcriptional activity. We first identified genes that are direct transcriptional targets of HSF1 utilizing more than 40 ChIP-Seq samples in the public domain. Genes identified from ChIP-Seq were then reduced by removing genes whose expression was not altered or showed increased expression with the knockdown of HSF1. These genes were then assessed for their correlation with every other gene across 11 cancer expression datasets to develop an adjacency matrix to identify subgroups of genes that have high inter-gene correlation. The resulting 23-gene set (HAS) was then tested for its performance of assessing HSF1 activity wherein it was found to decreased when HSF1 was knocked down and increase in response to heat shock. The HAS was also able to predict outcomes of breast cancer patients that are previously observed such as high HAS was associated with worse overall survival and metastasis-free survival. This association with cancer patient outcomes extended to many other tumor types. In total, the 23-gene set we termed HAS, is an accurate tool to assess HSF1 activity from transcript expression data that is not limited to cancer-related functions of HSF1.

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Section: Resultsmentioning

confidence: 99%

“…Fig. 9A), which is also a canonical chemoattractant cytokine for CD8+ T cells (39). The effect of HSF1 knockdown on CCL5 expression was confirmed with qPCR in both mouse and human breast cancer cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

HSF1 excludes CD8+ T cells from breast tumors via suppression of CCL5

Carpenter

Ray

Wang

et al. 2022

Preprint

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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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“…One of the most studied is CXCL10, a chemoattractant cytokine. By fixation on its receptor CXCR3, expressed at the cell surface of CD8, this molecule attracts CD8 T cells at the tumor site thus leading to tumor growth control 24 . CXCL10 production can be triggered by cancer cell‐derived type I IFN via an autocrine signaling loop 20 or after the engulfment of chemotherapy‐damaged mitochondria in autophagolysosmes and the sensing of released mitochondrial DNA by TLR9 25 .…”

Section: Immunogenic Cell Death Conceptmentioning

confidence: 99%

Using immunogenic cell death to improve anticancer efficacy of immune checkpoint inhibitors: From basic science to clinical application

Ghiringhelli,

Rébé

2023

Immunological Reviews

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SummaryEven though the discovery of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, a high proportion of patients do not respond. Moreover, some types of cancers are refractory to these treatments. Thus, the need to find predictive biomarkers of efficacy and to evaluate the association with other treatments, such as chemotherapy or radiotherapy, appears to be essential. Because ICIs reactivate or maintain an active status of T cells, one possibility is to combine these treatments with therapies that engage an immune response against tumor cells. Thus, by inducing immunogenic cell death (ICD) of cancer cells, some conventional anticancer treatments induce such immune response and may have an interest to be combined with ICIs. In this review, we explore preclinical studies and clinical trials that evaluate the combination of ICIs with ICD inducers. More than inducing ICD, some of these treatments appear to modulate the tumor microenvironment and more particularly to inhibit immunosuppression, thus improving treatment efficacy.

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Tumor Immunogenic Cell Death as a Mediator of Intratumor CD8 T-Cell Recruitment

Cited by 28 publications

References 166 publications

HSF1 excludes CD8+ T cells from breast tumors via suppression of CCL5

HSF1 excludes CD8+ T cells from breast tumors via suppression of CCL5

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

Using immunogenic cell death to improve anticancer efficacy of immune checkpoint inhibitors: From basic science to clinical application

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