scholarly journals Emerging role of SWI/SNF complex deficiency as a target of immune checkpoint blockade in human cancers

Oncogenesis ◽  
2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Min Zhou ◽  
Jianlong Yuan ◽  
Yaqi Deng ◽  
Xianqun Fan ◽  
Jianfeng Shen
Keyword(s):  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Cancer Therapeutics ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Human Cancers ◽  
Complex Deficiency ◽  
Specific Vulnerability ◽  
Underlying Mechanisms

AbstractMammalian SWI/SNF complex is a key chromatin remodeler that reshapes nucleosomes and regulates DNA accessibility. Mutations in SWI/SNF subunits are found in a broad spectrum of human cancers; however, the mechanisms of how these aberrations of SWI/SNF complex would impact tumorigenesis and cancer therapeutics remain to be elucidated. Studies have demonstrated that immune checkpoint blockade (ICB) therapy is promising in cancer treatment. Nevertheless, suitable biomarkers that reliably predict the clinical response to ICB are still lacking. Emerging evidence has suggested that SWI/SNF components play novel roles in the regulation of anti-tumor immunity, and SWI/SNF deficiency can be therapeutically targeted by ICB. These findings manifest the prominence of the SWI/SNF complex as a stratification biomarker that predicts treatment (therapeutic) response to ICB. In this review, we summarize the recent advances in ICB therapy by harnessing the cancer-specific vulnerability elicited by SWI/SNF deficiency. We provide novel insights into a comprehensive understanding of the underlying mechanisms by which SWI/SNF functions as a modulator of anti-tumor immunity.

scholarly journals Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
Author(s):  
Xiuting Liu ◽  
Graham D Hogg ◽  
David G DeNardo
Keyword(s):  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

scholarly journals The role of neoantigen in immune checkpoint blockade therapy

2018 ◽  
Vol 7 (1) ◽  
Author(s):  
Ming Yi ◽  
Shuang Qin ◽  
Weiheng Zhao ◽  
Shengnan Yu ◽  
Qian Chu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

Association of the diversity and composition of the gut microbiome with responses and survival (PFS) in metastatic melanoma (MM) patients (pts) on anti-PD-1 therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3008-3008 ◽  
Author(s):  
Jennifer Ann Wargo ◽  
Vancheswaran Gopalakrishnan ◽  
Christine Spencer ◽  
Tatiana Karpinets ◽  
Alexandre Reuben ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Large Cohort ◽  
Checkpoint Blockade ◽  
Cancer Types ◽  
Pre Treatment ◽  
Immune Profiling ◽  
Made In

3008 Background: Significant advances have been made in cancer therapy with immune checkpoint blockade. However, responses in pts with MM are variable, and insights are needed to identify biomarkers of response and strategies to overcome resistance. There is a growing appreciation of the role of the microbiome in cancer, and evidence in murine models that modulation of the gut microbiome may enhance responses to immune checkpoint blockade, though this has not been well studied in pts. Thus we evaluated the microbiome in a large cohort of pts with MM, focusing on responses to anti-PD-1. Methods: We collected oral (n = 234) and gut microbiome samples (n = 120) on a large cohort of of MM patients (n = 221). Of note, the majority of pts were treated with PD-1 based therapy (n = 105). Pts on anti-PD1 were classified as either responders (R) or non-responders (NR) based on RECIST criteria, and 16S rRNA and whole genome shotgun (WGS) sequencing were performed. Immune profiling (via immunohistochemistry, flow cytometry, cytokines and gene expression profiling) was also done in available pre-treatment tumors at baseline. Results: Significant differences in diversity and composition of the gut microbiome were noted in R vs NR to anti-PD-1, with a higher diversity of bacteria in R vs NR (p = 0.03). Differences were also noted in the composition of gut bacteria, with a higher abundance of Clostridiales in R and of Bacteroidales in NR. Immune profiling demonstrated increased tumor immune infiltrates in R pts , with a higher density of CD8+T cells; this correlated with abundance of specific bacteria enriched in the gut microbiome (r = 0.59, 0.014). Other features of enhanced immunity were also noted, and WGS revealed differential metabolic signatures in R vs NR. Furthermore, diversity (p = 0.009; HR = 7.67) and abundance of specific bacteria in R (p = 0.007; HR = 3.88) was associated with improved PFS to anti-PD-1 therapy. Conclusions: Diversity and composition of the gut microbiome differ in R vs NR pts with MM receiving anti-PD-1 therapy. These have potentially far-reaching implications, though results need to be validated in larger cohorts across cancer types.

SOX2 as a target for immunotherapy of pediatric gliomas.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e22012-e22012 ◽  
Author(s):  
Juan Vasquez ◽  
Anita Huttner ◽  
Lin Zhang ◽  
Asher Marks ◽  
Amy Chan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Cell Mass ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Low Grade ◽  
Glial Tumors

e22012 Background: New treatments are needed to improve outcomes for pediatric gliomas. Immune checkpoint inhibitors are effective therapies in tumors with a high mutation burden that express multiple neo-antigens. However, for pediatric tumors that carry few mutations, there is a need to identify new antigenic targets of anti-tumor immunity. SOX2 is an embryonal stem cell antigen implicated in the biology of glioma initiating cells. Expression of SOX2 by pediatric glial tumors, and the capacity of the immune system in these patients to recognize SOX2, has not been studied. Methods: We examined the expression of SOX2 on paraffin-embedded tissue from pediatric glial tumors (n = 30). The presence of T cell immunity to SOX2 was examined in both blood and tumor-infiltrating T cells using antigen-dependent cytokine and T cell proliferation assays (n = 15). The nature of tumor-infiltrating immune cells in glial tumors (n = 4) was analyzed using single cell mass cytometry. Results: SOX2 is expressed by tumor cells but not surrounding normal tissue in all low grade gliomas (n = 15), high grade gliomas (n = 7), ependymomas (n = 3) and in 60% of oligodendrogliomas (n = 5). T cells against SOX2 can be detected in blood and tumor tissue in 33% of patients. CD4 and CD8 tumor infiltrating T-cells display a higher proportion of PD-1 expression compared to circulating T cells (p < 0.05). Glial CD4 and CD8 T cells are enriched for tissue resident memory phenotype (TRM; CD45RO+, CD69+, CCR7-) and the expression of PD-1 is primarily on these TRM cells (p < 0.05). A subset of CD4 and CD8 TRM cells also co-express multiple inhibitory checkpoints including PD-L1 and TIGIT. Glial tumors also contain NK cells with reduced expression of lytic granzyme (p < 0.05). Conclusions: Our data demonstrate in vivo immunogenicity of SOX2, which is specifically overexpressed on pediatric glial tumor cells. Our data also suggest that the TRM subset of tumor-infiltrating T cells may be key targets for immune checkpoint blockade, and harnessing tumor immunity will likely require the combined targeting of multiple inhibitory checkpoints. Future efforts to target SOX2 with dendritic cell vaccines combined with immune checkpoint blockade could provide effective tumor immunity and improve outcomes in pediatric brain tumors.

scholarly journals Targeting Multiple Receptors to Increase Checkpoint Blockade Efficacy

2019 ◽  
Vol 20 (1) ◽  
pp. 158 ◽  
Author(s):  
David J. Zahavi ◽  
Louis M. Weiner
Keyword(s):  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Treatment Strategy ◽  
Immune Checkpoint Blockade ◽  
Tumor Formation ◽  
Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Multiple Receptors ◽  
Cancer Types ◽  
Receptor Targets

Immune checkpoint blockade therapy is a powerful treatment strategy for many cancer types. Many patients will have limited responses to monotherapy targeted to a single immune checkpoint. Both inhibitory and stimulatory immune checkpoints continue to be discovered. Additionally, many receptors previously identified to play a role in tumor formation and progression are being found to have immunomodulatory components. The success of immunotherapy depends on maximizing pro-anti-tumor immunity while minimizing immunosuppressive signaling. Combining immune checkpoint targeted approaches with each other or with other receptor targets is a promising schema for future therapeutic regimen designs.

The application of immune checkpoint blockade in breast cancer and the emerging role of nanoparticle

2021 ◽  
Author(s):  
Elham Masoumi ◽  
Sahar Tahaghoghi-Hajghorbani ◽  
Leila Jafarzadeh ◽  
Mohammad-Javad Sanaei ◽  
Atieh Pourbagheri-Sigaroodi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade
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