Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial

Voorwerk, Leonie; Slagter, Maarten; Horlings, Hugo M.; Sikorska, Karolina; Vijver, Koen K. Van de; Maaker, Michiel de; Nederlof, Iris; Kluin, Roelof J.C.; Warren, Sarah; Ong, SuFey; Wiersma, T.; Russell, Nicola S.; Lalezari, Ferry; Schouten, Philip C.; Bakker, Noor; Ketelaars, Steven L. C.; Peters, Dennis; Lange, Charlotte A.H.; Werkhoven, Erik van; Tinteren, Harm van; Mandjes, Ingrid A.M.; Kemper, Inge; Onderwater, Suzanne; Chalabi, Myriam; Wilgenhof, Sofie; Haanen, John B.A.G.; Salgado, Roberto; Visser, Karin E. de; Sonke, Gabe S.; Wessels, Lodewyk F.A.; Linn, Sabine C.; Schumacher, Ton N.; Blank, Christian U.; Kok, Marleen

doi:10.1038/s41591-019-0432-4

Cited by 665 publications

(595 citation statements)

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“…The TONIC trial on metastatic triple-negative breast cancer patients shows that doxorubicin or cisplatin allows tumors to have the capacity to respond to anti-PD-1. This was deduced from high response rates to anti-PD-1 and from upregulation of immune-related gene sets [116]. Cisplatin increased radiotherapy + immunotherapy (anti-PD-1 + anti-CD137) effects on tumor growth in a murine AT-3 breast cancer model [117].…”

Section: Platinum Derivatives and Immune Checkpointsmentioning

confidence: 99%

“…Breast Cancer anti-PD-1 patient response [116] HNSCC No effect on PD-L1 expression [118] NSCLC PD-L1 expression in patient biopsies [122] Paclitaxel/carboplatin/bevacizumab PD-1 and CTLA-4 on proliferating peripheral CD8 + T-cells [110] Even if platinum derivatives seem to induce PD-1/PD-L1 expression, some discrepancies were observed. This might be explained by the cell lines (more about the genetic background than tumor type) and compound concentrations used, or by a possible indirect effect of platinum derivatives on cancer cells or neighboring cells that will in turn regulate PD-L1 expression.…”

Section: Triple-negativementioning

confidence: 99%

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Platinum Derivatives Effects on Anticancer Immune Response

et al. 2019

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Along with surgery and radiotherapy, chemotherapeutic agents belong to the therapeutic arsenal in cancer treatment. In addition to their direct cytotoxic effects, these agents also impact the host immune system, which might enhance or counteract their antitumor activity. The platinum derivative compounds family, mainly composed of carboplatin, cisplatin and oxaliplatin, belongs to the chemotherapeutical arsenal used in numerous cancer types. Here, we will focus on the effects of these molecules on antitumor immune response. These compounds can induce or not immunogenic cell death (ICD), and some strategies have been found to induce or further enhance it. They also regulate immune cells' fate. Platinum derivatives can lead to their activation. Additionally, they can also dampen immune cells by selective killing or inhibiting their activity, particularly by modulating immune checkpoints' expression.Cell death is characterized by morphological alterations that have been historically used by The Nomenclature Committee on Cell Death (NCCD) to classify this cellular process into three different forms: type I or apoptosis, type II or autophagy, and type III or necrosis. Although limited, this morphological classification remains widely used, independently of essential molecular aspects of the cell death process. New NCCD classifications focus on molecular mechanisms and on the biochemistry of intracellular signalization effectors. Currently, it is clear that connections and overlaps exist between the different types of cell death. The majority of chemotherapeutic drugs are known to induce apoptosis or necrosis. Engagement of a particular type of cell death depends on the stress type, interaction between induction factors, genetic cell background, organelle content and enzymatic proteins arsenal [3,4].The action of chemotherapy relies not only on its cytotoxic effect on cancer cells, but also on its ability to affect immune cells.

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Section: Platinum Derivatives and Immune Checkpointsmentioning

confidence: 99%

Section: Triple-negativementioning

confidence: 99%

Platinum Derivatives Effects on Anticancer Immune Response

et al. 2019

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“…Furthermore, inhibition of specific DNA repair proteins (such as PARP1) has also been linked with immune activation [19]. In keeping with this, a number of groups have demonstrated stimulation of type 1 interferons and cytokines following treatment with DNA damaging agents or ionising radiation in both the in vitro and in vivo settings [4,8,9,20]. Similarly, a recent study screening a panel of FDA-approved drugs for agents that induce immunogenic cell death (ICD), identified the topo-II inhibitor teniposide as a potent ICD inducer [21].…”

Section: Discussionmentioning

confidence: 94%

“…In this study, patients were given no induction therapy or induction therapy with hypofractionated radiotherapy, cyclophosphamide, cisplatin or doxorubicin followed by 3-cycles of nivolumab. The highest response rate (35%) was seen in patients receiving induction doses of doxorubicin [27].…”

Section: Discussionmentioning

confidence: 97%

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Topoisomerase II inhibitors induce cGAS-STING dependent inflammation resulting in cytokine induction and immune checkpoint activation

Wilkinson

McCabe

Parkes

et al. 2019

Preprint

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Tumours with genomic instability demonstrate enhanced immunogenicity and potential for response to immune checkpoint blockade (ICB). We previously demonstrated activation of the cGAS-STING pathway following loss of DNA repair, resulting in cytokine induction, lymphocytic infiltration and immune checkpoint activation. Here we explore the role of chemotherapies in inducing this innate immune response, identifying topoisomerase II (topo-II) inhibitors, particularly doxorubicin and epirubicin, as potent inducers of a cGAS-STING dependent interferon response. Mechanistically, topo-II inhibition resulted in significant induction of cytoplasmic DNA and subsequent micronuclei formation, a requirement for efficient cGAS-STING activation and consequent cytokine and immune checkpoint gene induction. Importantly, increased cytokine and immune checkpoint gene expression, as well as increased immune cell infiltration, was also observed in patient derived breast tumour biopsies following topo-II inhibitor-based treatment. Taken together, this study indicates topo-II inhibitors such as doxorubicin, may be best placed to induce immunogenic inflammation, and thereby increase responses to ICB therapies. Running Title: Topoisomerase II inhibitors induce cGAS-STING activation SignificanceThis work demonstrates how topo-II inhibitors induce STING-pathway activation, cytokine induction and immune checkpoint protein upregulation in cancer cells and provides a rationale for combining topo-II inhibitors with ICB therapy in early breast cancer.3

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Human Leukocyte Antigen Class I Antigen-Processing Machinery Upregulation by Anticancer Therapies in the Era of Checkpoint Inhibitors

et al. 2022

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IMPORTANCEAlthough typically impressive, objective responses to immune checkpoint inhibitors (ICIs) occur in only 12.5% of patients with advanced cancer. The majority of patients do not respond due to cell-intrinsic resistance mechanisms, including human leukocyte antigen (HLA) class I antigen-processing machinery (APM) defects. The APM defects, which have a negative effect on neoantigen presentation to cytotoxic T lymphocytes (CTLs), are present in the majority of malignant tumors. These defects are caused by gene variations in less than 25% of cases and by dysregulated signaling and/or epigenetic changes in most of the remaining cases, making them frequently correctable. This narrative review summarizes the growing clinical evidence that chemotherapy, targeted therapies, and, to a lesser extent, radiotherapy can correct HLA class I APM defects in cancer cells and improve responses to ICIs.OBSERVATIONS Most chemotherapeutics enhance HLA class I APM component expression and function in cancer cells, tumor CTL infiltration, and responses to ICIs in preclinical and clinical models. Despite preclinical evidence, radiotherapy does not appear to upregulate HLA class I expression in patients and does not enhance the efficacy of ICIs in clinical settings. The latter findings underscore the need to optimize the dose and schedule of radiation and timing of ICI administration to maximize their immunogenic synergy. By increasing DNA and chromatin accessibility, epigenetic agents (histone deacetylase inhibitors, DNA methyltransferase inhibitors, and EZH2 inhibitors) enhance HLA class I APM component expression and function in many cancer types, a crucial contributor to their synergy with ICIs in patients. Furthermore, epidermal growth factor receptor (EGFR) inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors are effective at upregulating HLA class I expression in EGFR-and BRAF-variant tumors, respectively; these changes may contribute to the clinical responses induced by these inhibitors in combination with ICIs.CONCLUSIONS AND RELEVANCE This narrative review summarizes evidence indicating that chemotherapy and targeted therapies are effective at enhancing HLA class I APM component expression and function in cancer cells. The resulting increased immunogenicity and recognition and elimination of cancer cells by cognate CTLs contributes to the antitumor activity of these therapies as well as to their synergy with ICIs.

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Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial

Cited by 665 publications

References 57 publications

Platinum Derivatives Effects on Anticancer Immune Response

Platinum Derivatives Effects on Anticancer Immune Response

Topoisomerase II inhibitors induce cGAS-STING dependent inflammation resulting in cytokine induction and immune checkpoint activation

Human Leukocyte Antigen Class I Antigen-Processing Machinery Upregulation by Anticancer Therapies in the Era of Checkpoint Inhibitors

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