Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40

Yang, Yan; Liu, Chengwen; Peng, Weiyi; Lizée, Gregory; Overwijk, Willem W.; Liu, Yang; Woodman, Scott E.; Hwu, Patrick

doi:10.1182/blood-2012-02-407163

Cited by 57 publications

(67 citation statements)

References 50 publications

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“…Bacterial infection or viral reactivation such as cytomegalovirus, which has been reported to be associated with dasatinibinduced hyperleukocytosis, 6 would qualify as the inflammatory trigger. In concert with the described inhibition of regulatory T cells by dasatinib, as reported in vitro 41 and in vivo, 42 these mechanisms may lead to unrestricted CD8 proliferation in the clinical setting, along with a better clinical response against the underlying leukemic disease. 5,43 The exact regulation of IL-12 synthesis on TLR-mediated activation in DCs is still not fully understood.…”

Section: Discussionmentioning

confidence: 75%

Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor–induced interleukin 12 synthesis

Wölfl

Schwinn²,

Yoo

et al. 2013

Blood

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• In contrast to their suppressive effects on T cells, src-kinase inhibitors strongly enhance IL-12 production in human myeloid cells. • This effect is synergistic to TLR2 or TLR4 signaling, whereas inhibition of srckinases alone does not trigger DC activation.Src-kinase inhibitors hold great potential as targeted therapy against malignant cells. However, such inhibitors may also affect nonmalignant cells and cause pronounced offtarget effects. We investigated the role of the dual kinase inhibitor dasatinib on human myeloid cells. Dasatinib is clinically used for the treatment of bcr/abl 1 leukemias because it blocks the mutated tyrosine kinase abl. To understand its effect on the development of antigen-specific T-cell responses, we assessed antigen-specific priming of human, naïve T cells. In surprising contrast to the direct inhibition of T-cell activation by dasatinib, pretreatment of maturing dendritic cells (DCs) with dasatinib strongly enhanced their stimulatory activity. This effect strictly depended on the activating DC stimulus and led to enhanced interleukin 12 (IL-12) production and T-cell responses of higher functional avidity. Src-kinase inhibitors, and not conventional tyrosine kinase inhibitors, increased IL-12 production in several cell types of myeloid origin, such as monocytes and classical or nonclassical DCs. Interestingly, only human cells, but not mouse or macaques DCs, were affected. These data highlight the potential immunostimulatory capacity of a group of novel drugs, src-kinase inhibitors, thereby opening new opportunities for chemoimmunotherapy. These data also provide evidence for a regulatory role of src kinases in the activation of myeloid cells. (Blood. 2013;122(7):1203-1213

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Section: Discussionmentioning

confidence: 75%

Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor–induced interleukin 12 synthesis

Wölfl

Schwinn²,

Yoo

et al. 2013

Blood

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“…Dasatinib doses administered to CML patients achieve serum concentrations sufficient to inhibit SIKs and to up-regulate IL-10 by activated DCs (28), which suggests that SIK inhibition is unlikely to be toxic and that the IL-10-potentiating activity of FDAapproved drugs targeting these kinases might be explored as candidate treatments for IBD. In the context of cancer, it is possible that elevated serum IL-10 levels mediated by SIK inhibition could modulate the chemotherapeutic activity of dasatinib given that T-cell-mediated immune responses targeting tumor antigens are a critical component of dasatinib's mode-of-action (29). Therefore, combining dasatinib or related kinase inhibitors with an IL-10 neutralizing strategy might be a rational approach to enhance the chemotherapeutic activity of these compounds.…”

Section: Discussionmentioning

confidence: 99%

Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells

Sundberg

Choi

Song

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Genetic alterations that reduce the function of the immunoregulatory cytokine IL-10 contribute to colitis in mouse and man. Myeloid cells such as macrophages (MΦs) and dendritic cells (DCs) play an essential role in determining the relative abundance of IL-10 versus inflammatory cytokines in the gut. As such, using small molecules to boost IL-10 production by DCs-MΦs represents a promising approach to increase levels of this cytokine specifically in gut tissues. Toward this end, we screened a library of wellannotated kinase inhibitors for compounds that enhance production of IL-10 by murine bone-marrow-derived DCs stimulated with the yeast cell wall preparation zymosan. This approach identified a number of kinase inhibitors that robustly up-regulate IL-10 production including the Food and Drug Administration (FDA)-approved drugs dasatinib, bosutinib, and saracatinib that target ABL, SRC-family, and numerous other kinases. Correlating the kinase selectivity profiles of the active compounds with their effect on IL-10 production suggests that inhibition of salt-inducible kinases (SIKs) mediates the observed IL-10 increase. This was confirmed using the SIK-targeting inhibitor HG-9-91-01 and a series of structural analogs. The stimulatory effect of SIK inhibition on IL-10 is also associated with decreased production of the proinflammatory cytokines IL-1β, IL-6, IL-12, and TNF-α, and these coordinated effects are observed in human DCs-MΦs and anti-inflammatory CD11c + CX 3 CR1 hi cells isolated from murine gut tissue. Collectively, these studies demonstrate that SIK inhibition promotes an anti-inflammatory phenotype in activated myeloid cells marked by robust IL-10 production and establish these effects as a previously unidentified activity associated with several FDA-approved multikinase inhibitors.

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“…One explanation may be the location of the tumor in the models used, including subcutaneous, skin and lungs, as well as the timing of targeted therapy in relation to immune cell depletion. Similarly, imatinib efficacy is dependent on NK cells in melanoma metastasis models [128], whereas CD8 + T cells contribute to tumor regression following imatinib treatment of GIST-bearing mice or dasatinib treatment of subcutaneous mastocytoma-bearing mice [129,130].…”

Section: Adaptive Immune Cellsmentioning

confidence: 99%

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

125

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SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

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Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40

Cited by 57 publications

References 50 publications

Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor–induced interleukin 12 synthesis

Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor–induced interleukin 12 synthesis

Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

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