ΔNp63-driven recruitment of myeloid-derived suppressor cells promotes metastasis in triple-negative breast cancer

Kumar, Sushil; Wilkes, David W.; Samuel, Nina; Blanco, Mario Andres; Nayak, Anupma; Alicea-Torres, Kevin; Gluck, Christian; Sinha, Satrajit; Gabrilovich, Dmitry I.; Chakrabarti, Rumela

doi:10.1172/jci99673

Cited by 121 publications

(109 citation statements)

References 63 publications

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“…Immune checkpoint signaling depends on crosstalk between the cancer cell, T cells, myeloid‐derived suppressor cells (MDSCs), tumor‐associated macrophages (TAMs), dendritic cells (DCs), natural killer T cells (NKT), among others 20‐205 . PD‐L1 is expressed on tumor epithelial cells, T cells, TAMs, DCs, MDSCs, other immune cells and stromal cells such as adipocytes, which implies a complex biology 22‐207 . For example, PD‐L1 concentration correlates with FoxP3+ regulatory T cells (Tregs) which create an immunosuppressive tumor microenvironment, especially in basal‐like TNBC and even in early lesions including basal‐like ductal carcinoma in situ (DCIS) 28,209 .…”

Section: Anti‐tumor Immunitymentioning

confidence: 99%

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

Sipe

Chaib

Pingili

et al. 2020

Immunological Reviews

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Bile acids (BAs) are known facilitators of nutrient absorption but recent paradigm shifts now recognize BAs as signaling molecules regulating both innate and adaptive immunity. Bile acids are synthesized from cholesterol in the liver with subsequent microbial modification and fermentation adding complexity to pool composition. Bile acids act on several receptors such as Farnesoid X Receptor and the G proteincoupled BA receptor 1 (TGR5). Interestingly, BA receptors (BARs) are expressed on immune cells and activation either by BAs or BAR agonists modulates innate and adaptive immune cell populations skewing their polarization toward a more tolerogenic anti-inflammatory phenotype. Intriguingly, recent evidence also suggests that BAs promote anti-tumor immune response through activation and recruitment of tumoricidal immune cells such as natural killer T cells. These exciting findings have redefined BA signaling in health and disease wherein they may suppress inflammation on the one hand, yet promote anti-tumor immunity on the other hand. In this review, we provide our readers with the most recent understanding of the interaction of BAs with the host microbiome, their effect on innate and adaptive immunity in health and disease with a special focus on obesity, bariatric surgery-induced weight loss, and immune checkpoint blockade in cancer. K E Y W O R D S bariatric surgery, immunometabolism, microbiome, mitochondria, obesity, tumor microenvironment | 221 SIPE Et al.

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Section: Anti‐tumor Immunitymentioning

confidence: 99%

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

Sipe

Chaib

Pingili

et al. 2020

Immunological Reviews

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“…The chemokine expression level supporting intratumor MDSC recruitment has been found to be regulated by transcription factors. A high level of ΔNp63 in triple-negative breast cancer (TNBC) is positively correlated with the size of the MDSC population, which represents a direct ΔNp63-dependent activation of chemokines such as CXCL2 and CCL22 [86]. CXCR2 + PMN-MDSCs enhance tumor growth, whereas their migration from the periphery to the tumor appears to be dependent on CXCR2.…”

Section: Myeloid-derived Suppressor Cellsmentioning

confidence: 99%

Modeling of the immune response in the pathogenesis of solid tumors and its prognostic significance

2020

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Background Tumor initiation and subsequent progression are usually long-term processes, spread over time and conditioned by diverse aspects. Many cancers develop on the basis of chronic inflammation; however, despite dozens of years of research, little is known about the factors triggering neoplastic transformation under these conditions. Molecular characterization of both pathogenetic states, i.e., similarities and differences between chronic inflammation and cancer, is also poorly defined. The secretory activity of tumor cells may change the immunophenotype of immune cells and modify the extracellular microenvironment, which allows the bypass of host defense mechanisms and seems to have diagnostic and prognostic value. The phenomenon of immunosuppression is also present during chronic inflammation, and the development of cancer, due to its duration, predisposes patients to the promotion of chronic inflammation. The aim of our work was to discuss the above issues based on the latest scientific insights. A theoretical mechanism of cancer immunosuppression is also proposed. Conclusions Development of solid tumors may occur both during acute and chronic phases of inflammation. Differences in the regulation of immune responses between precancerous states and the cancers resulting from them emphasize the importance of immunosuppressive factors in oncogenesis. Cancer cells may, through their secretory activity and extracellular transport mechanisms, enhance deterioration of the immune system which, in turn, may have prognostic implications.

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“…As such, immune suppression could likely have occurred before day 14 within the tumor site in mice bearing AdIL-17A-transduced tumors, which had much faster kinetics of MDSC expansion compared to the control group. In breast cancer patients, TNBC samples are found to have a significantly increased number of MDSCs compared to non-TNBC counterparts 65 . Increased expression of the oncogenic p63 isoform has been identified as a culprit for triggering an increased MDSC recruitment through CXCL2- and CCL22-dependent mechanisms 65 .…”

Section: Discussionmentioning

confidence: 99%

Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas

Dawod

Liu

Gebremeskel

et al. 2020

Sci Rep

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Triple-negative breast cancer (TNBC) is an invasive subtype of breast cancer but paradoxically associated with increased tumor-infiltrating leukocytes. The molecular and cellular mechanisms underlying TNBC immunobiology are incompletely understood. Interleukin (IL)-17A is a pro-inflammatory cytokine that has both pro- and anti-tumor effects and found in 40–80% of TNBC samples. We report here that IL-17A mRNA and protein are detectable in some human TNBC cell lines and further upregulated by IL-23 and LPS stimulation. Furthermore, the impact of tumor-derived IL-17A in host immune response and tumor growth was examined using murine TNBC 4T1 mammary carcinoma cells transduced with an adenoviral vector expressing IL-17A (AdIL-17A) or control vector (Addl). Compared to Addl-transduction, AdIL-17A-transduction enhanced 4T1 tumor growth and lung metastasis in vivo, which was associated with a marked expansion of myeloid-derived suppressor cells (MDSCs). However, AdIL-17A-transduction also induced strong organ-specific and time-dependent immune activation indicated by dynamic changes of NK cells, B cells, CD4, and CD8 T cells in peripheral blood, lung, and tumor site, as well as the plasma levels of IFNγ. Such findings highlight that tumor-associated IL-17A induces concurrent immune activation and immune suppression. Administration of anti-Gr1 or anti-G-CSF antibody effectively depleted MDSCs in vivo, markedly reducing the growth of AdIL-17A-transduced 4T1 tumors, and eliminating lung metastasis. Collectively, our study demonstrates that MDSC depletion is an effective and practical approach for treating IL-17A-enriched mammary carcinomas.

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ΔNp63-driven recruitment of myeloid-derived suppressor cells promotes metastasis in triple-negative breast cancer

Cited by 121 publications

References 63 publications

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

Modeling of the immune response in the pathogenesis of solid tumors and its prognostic significance

Myeloid-derived suppressor cell depletion therapy targets IL-17A-expressing mammary carcinomas

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