Cancer immunotherapy and the value of cure

Paggio, Joseph C Del

doi:10.1038/nrclinonc.2018.27

Cited by 124 publications

(90 citation statements)

References 10 publications

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“…Recently, immunotherapy has become a powerful clinical strategy for cancer therapy [53][54][55]. Levels of MDSCs, NO and ROS in the peripheral blood are critical biomarkers for monitoring the immune system response and the overall success of immunotherapy [56].…”

Section: Discussionmentioning

confidence: 99%

Green Tea Polyphenol EGCG Attenuates MDSCs-mediated Immunosuppression through Canonical and Non-Canonical Pathways in a 4T1 Murine Breast Cancer Model

Yan

Zhao

et al. 2020

Nutrients

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Several studies in the past decades have reported anti-tumor activity of the bioactive compounds extracted from tea leaves, with a focus on the compound epigallocatechin-3-gallate (EGCG). However, further investigations are required to unravel the underlying mechanisms behind the anti-tumor activity of EGCG. In this study, we demonstrate that EGCG significantly inhibits the growth of 4T1 breast cancer cells in vitro and in vivo. EGCG ameliorated immunosuppression by significantly decreasing the accumulation of myeloid-derived suppressor cells (MDSCs) and increasing the proportions of CD4+ and CD8+ T cells in spleen and tumor sites in 4T1 breast tumor-bearing mice. Surprisingly, a low dose of EGCG (0.5–5 μg/mL) effectively reduced the cell viability and increased the apoptosis rate of MDSCs in vitro. EGCG down-regulated the canonical pathways in MDSCs, mainly through the Arg-1/iNOS/Nox2/NF-κB/STAT3 signaling pathway. Moreover, transcriptomic analysis suggested that EGCG also affected the non-canonical pathways in MDSCs, such as ECM–receptor interaction and focal adhesion. qRT-PCR further validated that EGCG restored nine key genes in MDSCs, including Cxcl3, Vcan, Col4a1, Col8a1, Oasl2, Mmp12, Met, Itsnl and Acot1. Our results provide new insight into the mechanism of EGCG-associated key pathways/genes in MDSCs in the murine breast tumor model.

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Section: Discussionmentioning

confidence: 99%

Green Tea Polyphenol EGCG Attenuates MDSCs-mediated Immunosuppression through Canonical and Non-Canonical Pathways in a 4T1 Murine Breast Cancer Model

Yan

Zhao

et al. 2020

Nutrients

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“…1,2 Current immuno-oncology therapies can demonstrate tremendous efficacy and induce long-term remission in patients. 3 However, responses to immunotherapy are often restricted to a subset of cancers, for reasons that are not entirely understood.…”

Section: Introductionmentioning

confidence: 99%

Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

et al. 2018

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Cancers progress when the immune system fails to identify and eliminate malignant cells. Recognition of this, combined with advances in tumor immunology, has allowed development of therapies that induce effective anti-tumor immune responses. For incompletely-understood reasons, effective responses to immunotherapy occur in some patients and not others. Head and neck squamous cell carcinomas (HNSCC) are a common cancer type that can be divided into two subsets based on human papillomavirus (HPV) status. HPV status is a strong predictor of positive clinical outcome. Expression of exogenous viral antigens by HPV+, but not HPV-, HNSCC allows direct comparison of the immune status (immune cell presence and characteristics) between these two otherwise anatomically-similar tumors. Using TCGA data, we compared the immune landscape between HPV+ and HPV- treatment-naïve HNSCC. As compared to HPV- samples, HPV+ HNSCC exhibited a strong Th1 response characterized by increased infiltration with multiple types of immune cells and expression of their effector molecules. HPV+ HNSCC also expressed higher levels of CD39 and multiple T-cell exhaustion markers including LAG3, PD1, TIGIT, and TIM3 compared to HPV- HNSCC. Importantly, patients with higher expression of these exhaustion markers–indicative of a T-cell-inflamed tumor–correlated with markedly improved survival in HPV+, but not HPV-, HNSCC. Thus, profound differences exist between the immune landscape of HPV+ and HPV- HNSCC. These results suggest that immune checkpoint inhibitor therapy is a promising treatment strategy for HPV+ HNSCC, and that expression of immune checkpoint molecules could serve as a predictive biomarker of patient outcome in HPV+ HNSCC.

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“…Recently, cancer immunotherapy has shown high efficacy in treating a variety of cancers [9]. Particularly, the blockade of immune checkpoints is achieving rapid clinical successes in various advanced malignancies such as melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin’s lymphoma, bladder cancer, head and neck cancer, and the cancers with DNA mismatch-repair (MMR) deficiency [10].…”

Section: Introductionmentioning

confidence: 99%

TP53mutations promote immunogenic activity in breast cancer

Liu

Jiang

Gao

et al. 2018

Preprint

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Background: Although immunotherapy has recently achieved clinical successes in a variety of cancers, thus far there is no any immunotherapeutic strategy for breast cancer (BC). Thus, it is important to discover biomarkers for identifying the BC patients responsive to immunotherapy. TP53 mutations were often associated with worse clinical outcome in BC, of which the triple-negative BC (TNBC) has a high TP53 mutation rate (approximately 80%). TNBC is high-risk due to its high invasiveness, and lack of targeted therapy. To explore a potentially promising therapeutic option for the TP53-mutated BC subtype, we studied the associations between TP53 mutations and immunogenic activity in BC. Methods:We compared enrichment levels of 26 immune gene-sets that indicated activities of diverse immune cells, functions, and pathways between TP53-mutated and TP53-wildtype BCs based on two large-scale BC multi-omics data. Moreover, we explored the molecular cues that were associated with the differences in immunogenic activity between TP53-mutated and TP53-wildtype BCs. Furthermore, we performed experimental validation of the findings from bioinformatics analysis. Results:We found that almost all analyzed immune gene-sets had significantly higher enrichment levels in TP53-mutated BCs compared to TP53-wildtype BCs. Moreover, our experiments confirmed that mutant p53 could increase BC immunogenicity. Furthermore, our computational and experimental results showed that TP53 mutations could promote BC immunogenicity via regulation of the p53-mediated pathways including cell cycle, apoptosis, Wnt, Jak-STAT, NOD-like receptor, and glycolysis. Interestingly, we found that elevated immune activities were likely to be associated with better survival prognosis in TP53-mutated BCs, but not necessarily in TP53-wildtype BCs.Conclusions: TP53 mutations promote immunogenic activity in breast cancer. This finding demonstrates a different effect of p53 dysfunction on tumor immunogenicity from that of previous studies, suggesting that the TP53 mutation status could be a useful biomarker for stratifying BC patients responsive to immunotherapy. KeywordsTP53 mutations; breast cancer; tumor immunogenicity; immunological pathways; cancer omics BackgroundThe tumor suppressor p53 plays an important role in cell-cycle regulation, apoptosis, DNA repair, cellular senescence, and autophagy [1]. Accordingly, TP53 mutations and dysfunction are importantly involved in carcinogenesis due to the disturbance of these biologic processes it functions in. In fact, TP53 mutations occur in more than half of all human cancer cases [2], and are independent markers of poor prognosis in a variety of cancers [3]. P53 also plays an important role in immune regulation, e.g., the control of immune responses to infection, autoimmunity and cancer [4]. P53 functions in immunity by induction of apoptosis, removal of apoptotic cells, antiviral defense, induction of type I IFN, enhanced pathogen recognition, cytokine production, and immune checkpoint regulation [4]. Several studies ha...

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Cancer immunotherapy and the value of cure

Cited by 124 publications

References 10 publications

Green Tea Polyphenol EGCG Attenuates MDSCs-mediated Immunosuppression through Canonical and Non-Canonical Pathways in a 4T1 Murine Breast Cancer Model

Green Tea Polyphenol EGCG Attenuates MDSCs-mediated Immunosuppression through Canonical and Non-Canonical Pathways in a 4T1 Murine Breast Cancer Model

Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

TP53mutations promote immunogenic activity in breast cancer

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