WEE1 inhibition induces anti-tumor immunity by activating ERV and the dsRNA pathway

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Ensong Guo ◽  
Rourou Xiao ◽  
Yifan Wu ◽  
Funian Lu ◽  
Chen Liu ◽  
...  
Keyword(s):  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Interferon Response ◽  
Dependent Manner ◽  
Multiple Cancer ◽  
Multiple Tumor ◽  
Cancer Types

Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or to interdict the emergence of resistance. We demonstrate that targeting WEE1 up-regulates immune signaling through the double-stranded RNA (dsRNA) viral defense pathway with subsequent responsiveness to immune checkpoint blockade even in cGAS/STING-deficient tumors, which is a typical phenotype across multiple cancer types. WEE1 inhibition increases endogenous retroviral elements (ERVs) expression by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1. ERVs trigger dsRNA stress and interferon response, increasing recruitment of anti-tumor T cells with concurrent PD-L1 elevation in multiple tumor models. Furthermore, combining WEE1 inhibition and PD-L1 blockade induced striking tumor regression in a CD8+ T cell–dependent manner. A WEE1 inhibition–induced viral defense signature provides a potentially informative biomarker for patient selection for combination therapy with WEE1 and ICB. WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB, providing a rationale for the combination of WEE1 inhibitors and ICB in clinical trials.

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.

Improved prediction of immune checkpoint blockade efficacy across multiple cancer types

2021 ◽  
Author(s):  
Diego Chowell ◽  
Seong-Keun Yoo ◽  
Cristina Valero ◽  
Alessandro Pastore ◽  
Chirag Krishna ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Multiple Cancer ◽  
Cancer Types

scholarly journals Radiotherapy-Mediated Immunomodulation and Anti-Tumor Abscopal Effect Combining Immune Checkpoint Blockade

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2762 ◽  
Author(s):  
Xinrui Zhao ◽  
Chunlin Shao
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Combined Therapy ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Abscopal Effect ◽  
Specific Circumstance

Radiotherapy (RT) is a conventional method for clinical treatment of local tumors, which can induce tumor-specific immune response and cause the shrinkage of primary tumor and distal metastases via mediating tumor infiltration of CD8+ T cells. Ionizing radiation (IR) induced tumor regression outside the radiation field is termed as abscopal effect. However, due to the mobilization of immunosuppressive signals by IR, the activated CD8+T cells are not sufficient to maintain a long-term positive feedback to make the tumors regress completely. Eventually, the “hot” tumors gradually turn to “cold”. With the advent of emerging immunotherapy, the combination of immune checkpoint blockade (ICB) and local RT has produced welcome changes in stubborn metastases, especially anti-PD-1/PD-L1 and anti-CTLA-4 which have been approved in clinical cancer treatment. However, the detailed mechanism of the abscopal effect induced by combined therapy is still unclear. Therefore, how to formulate a therapeutic schedule to maximize the efficacy should be took into consideration according to specific circumstance. This paper reviewed the recent research progresses in immunomodulatory effects of local radiotherapy on the tumor microenvironment, as well as the unique advantage for abscopal effect when combined with ICB, with a view to exploring the potential application value of radioimmunotherapy in clinic.

scholarly journals 191 Tumor antigen (TA) specific Th1 cells combined with immune checkpoint blockade induces tumor regression even in mice with progressed cancer

2016 ◽  
Vol 136 (9) ◽  
pp. S193
Author(s):  
B.F. Schörg ◽  
D. Krüger ◽  
C.M. Griessinger ◽  
L. Quintanilla-Martinez ◽  
M. Schaller ◽  
...  
Keyword(s):  
Tumor Antigen ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Th1 Cells

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 the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jianhuang Lin ◽  
Heng Liu ◽  
Takeshi Fukumoto ◽  
Joseph Zundell ◽  
Qingqing Yan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Er Stress Response

AbstractCARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

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