IAP Antagonists Enhance Cytokine Production from Mouse and Human iNKT Cells

Clancy‐Thompson, Eleanor; Ali, Lestat; Bruck, Patrick T.; Exley, Mark A.; Blumberg, Richard S.; Dranoff, Glenn; Dougan, Michael; Dougan, Stephanie K.

doi:10.1158/2326-6066.cir-17-0490

Cited by 28 publications

(30 citation statements)

References 55 publications

(92 reference statements)

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“…T cells are another source of TNFα 49 , which could explain why CAT-T cells synergize with an IAP antagonist to treat cancer 50 . In particular, IAP antagonists can augment human and mouse T cell responses and cytokine production to physiologically relevant stimuli 51,52 . Thus, T cell deficiency in nude mice could be another reason why SM-164 alone had limited efficacy in mice with advanced BC metastases.…”

Section: Discussionmentioning

confidence: 99%

The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice

Lei

Duan

et al. 2020

Sci Rep

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The most challenging issue for breast cancer (BC) patients is metastasis to other organs because current therapies do not prevent or eliminate metastatic BC. Here, we show that SM-164, a small molecule inhibitor, which degrades inhibitor of apoptosis proteins (IAPs), eliminated early-stage metastases and reduced progression of advanced BC metastasis from MDA-MB-231 BC cells in bones and lungs of nude mice. Mechanistically, SM-164-induced BC cell death is TNFα-dependent, with TNFα produced by IL-4-polarized macrophages triggering MDA-MB-231 cell apoptosis in combination with SM-164. SM-164 also inhibited expression of RANKL, which mediates interactions between metastatic BC and host microenvironment cells and induces osteoclast-mediated osteolysis. SM-164 did not kill adriamycinresistant BC cells, while adriamycin inhibited SM-164-resistant BC cell growth, similar to parental cells. We conclude that SM-164 is a promising therapeutic agent for early stage bone and lung metastasis from triple-negative breast cancer that should be given prior to conventional chemotherapy. Breast cancer (BC) accounts for nearly a quarter of all cancers in women worldwide. It is estimated that 268,600 women will be diagnosed with invasive BC in the US in 2019 and 41,760 will die from it 1. The most challenging issue for patients with BC is metastasis to other organs, including bone, lung, liver and brain; this causes about 90% of BC deaths. For decades, BC treatment has included surgery, radiation therapy (RT), chemotherapy (CT), and/or hormonal therapy. However, none of the current therapies effectively prevents or eliminates BC. Adjuvant CT benefits only a small proportion (5-10%) of patients 2. Similarly, RT has resulted in only a 5% reduction in the 15-year BC mortality rate 3. One reason for the poor therapeutic outcome could be that many patients already have micro-metastases when their primary cancers are diagnosed 4-6. Bone metastases are distinct from metastases to other organs because of cancer-associated osteolysis due to enhanced osteoclast (OC) formation and activity and associated release of cancer-promoting proteins from the resorbed bone matrix, including TGFβ 7,8. Current standard anti-resorptive drugs (bisphosphonates and the RANKL inhibitor, denosumab) inhibit bone resorption and reduce skeletal-related events (SREs) 9,10 , but they do not prolong patient survival, and 30-50% of BC patients on these drugs still develop new bone metastases 9,11,12. The development and progression of BC metastases depend on interactions between the cancer cells and the host organ microenvironment. For example, circulating cancer cells can be attracted to bone by osteoblasts (OBs) or their progenitors, mesenchymal stem cells (MSCs), by expression of proteins, such as integrins, chemokines, Notch, nestin, and osteopontin by these cells 12 , and also via interactions between RANKL on OBs/MSCs and RANK expressed by cancer cells 13,14. Cancer cells in turn promote OB/MSC production of more RANKL to enhance OC formation, causing osteolysis 1...

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Section: Discussionmentioning

confidence: 99%

The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice

Lei

Duan

et al. 2020

Sci Rep

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“…7,[16][17][18][19] In addition to their pro-apoptotic properties, emerging data now suggests that IAP antagonists may have beneficial effects on multiple aspects of anti-tumor immunity. 8,[20][21][22][23][24][25][26] ASTX660 is a synthetic small molecule antagonist of IAPs, leading to degradation of cIAP1/2 and inhibition of XIAP. 27 Our prior work in the mouse oral cancer 1 (MOC1) syngeneic mouse model showed ASTX660 to be highly efficacious when paired with radiation and/or anti-PD-1 immune checkpoint blockade.…”

Section: Introductionmentioning

confidence: 99%

ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer

Gunti

Allen

et al. 2020

OncoImmunology

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“…We used somatic cell nuclear transfer to generate three independent lines of transnuclear (TN) mice, all of which use the identical Vα14Jα18 TCRα chain, but with three distinct TCRβ rearrangements (Clancy‐Thompson et al , , ). When crossed to C57BL/6 mice, the TN TCR alleles segregate independently, which allowed us to establish a line of Vα14 TN mice that inherited only the rearranged TCRα locus and therefore develop polyclonal iNKT cells.…”

Section: Resultsmentioning

confidence: 99%

Transnuclear mice reveal Peyer's patch iNKT cells that regulate B‐cell class switching to IgG1

et al. 2019

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Tissue‐resident iNKT cells maintain tissue homeostasis and peripheral surveillance against pathogens; however, studying these cells is challenging due to their low abundance and poor recovery from tissues. We here show that iNKT transnuclear mice, generated by somatic cell nuclear transfer, have increased tissue resident iNKT cells. We examined expression of PLZF, T‐bet, and RORγt, as well as cytokine/chemokine profiles, and found that both monoclonal and polyclonal iNKT cells differentiated into functional subsets that faithfully replicated those seen in wild‐type mice. We detected iNKT cells from tissues in which they are rare, including adipose, lung, skin‐draining lymph nodes, and a previously undescribed population in Peyer's patches (PP). PP‐NKT cells produce the majority of the IL‐4 in Peyer's patches and provide indirect help for B‐cell class switching to IgG1 in both transnuclear and wild‐type mice. Oral vaccination with α‐galactosylceramide shows enhanced fecal IgG1 titers in iNKT cell‐sufficient mice. Transcriptional profiling reveals a unique signature of PP‐NKT cells, characterized by tissue residency. We thus define PP‐NKT as potentially important for surveillance for mucosal pathogens.

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IAP Antagonists Enhance Cytokine Production from Mouse and Human iNKT Cells

Cited by 28 publications

References 55 publications

The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice

The IAP Antagonist SM-164 Eliminates Triple-Negative Breast Cancer Metastasis to Bone and Lung in Mice

ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer

Transnuclear mice reveal Peyer's patch iNKT cells that regulate B‐cell class switching to IgG1

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