scholarly journals c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chimera Lyle ◽  
Sean Richards ◽  
Kei Yasuda ◽  
Marc Arthur Napoleon ◽  
Joshua Walker ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Ring Finger ◽  
Neutralizing Antibody ◽  
Proteasomal Degradation ◽  
Negative Regulator ◽  
C Terminus ◽  
Fold Reduction ◽  
Programmed Cell Death 1

AbstractCasitas B lymphoma (c-Cbl) is an E3 ubiquitin ligase and a negative regulator of colorectal cancer (CRC). Despite its high expression in immune cells, the effect of c-Cbl on the tumor microenvironment remains poorly understood. Here we demonstrate that c-Cbl alters the tumor microenvironment and suppresses Programmed cell death-1 (PD-1) protein, an immune checkpoint receptor. Using syngeneic CRC xenografts, we observed significantly higher growth of xenografts and infiltrating immune cells in c-Cbl+/− compared to c-Cbl+/+ mice. Tumor-associated CD8+ T-lymphocytes and macrophages of c-Cbl+/− mice showed 2–3-fold higher levels of PD-1. Functionally, macrophages from c-Cbl+/− mice showed a 4–5-fold reduction in tumor phagocytosis, which was restored with an anti-PD-1 neutralizing antibody suggesting regulation of PD-1 by c-Cbl. Further mechanistic probing revealed that C-terminus of c-Cbl interacted with the cytoplasmic tail of PD-1. c-Cbl destabilized PD-1 through ubiquitination- proteasomal degradation depending on c-Cbl’s RING finger function. This data demonstrates c-Cbl as an E3 ligase of PD-1 and a regulator of tumor microenvironment, both of which were unrecognized components of its tumor suppressive activity. Advancing immune checkpoint and c-Cbl biology, our study prompts for probing of PD-1 regulation by c-Cbl in conditions driven by immune checkpoint abnormalities such as cancers and autoimmune diseases.

scholarly journals A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. Farias ◽  
A. Soto ◽  
F. Puttur ◽  
C. J. Goldin ◽  
S. Sosa ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Therapeutic Effect ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Combined Treatment ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Regulatory Cells ◽  
Ifn Γ

AbstractBrucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

scholarly journals Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden

2017 ◽  
Vol 114 (51) ◽  
pp. E10981-E10990 ◽  
Author(s):  
Meredith L. Stone ◽  
Katherine B. Chiappinelli ◽  
Huili Li ◽  
Lauren M. Murphy ◽  
Meghan E. Travers ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Histone Deacetylase Inhibitors ◽  
Unmet Need ◽  
Tumor Burden ◽  
Epigenetic Therapy ◽  
Type I ◽  
Type I Ifn

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

scholarly journals RARE-34. TUMOR IMMUNITY AND EXTRACRANIAL METASTASES, AND MECHANISM OF PD-L1 EXPRESSION IN INTRACRANIAL SOLITARY FIBROUS TUMOR/HEMANGIOPERICYTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi228-vi229
Author(s):  
Dai Kamamoto ◽  
Kentaro Ohara ◽  
Yohei Kitamura ◽  
Kazunari Yoshida ◽  
Hikaru Sasaki
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Immunity ◽  
Solitary Fibrous Tumor ◽  
Immune Checkpoint ◽  
Progression Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Free Survival ◽  
C Terminus ◽  
Fibrous Tumor ◽  
Extracranial Metastases

Abstract Intracranial solitary fibrous tumor (SFT) /hemangiopericytoma (HPC) are rare, however, these tumors are often associated with aggressive clinical course with recurrence and/or extracranial metastasis. PD-1, PD-L1 play important roles as immune-checkpoint mediators within tumor microenvironment, and the antibodies to these molecules are now approved for the treatment of various kinds of cancers. Some mechanisms of activation of PD-L1 are reported, including cytokines or chemokines from immune cells in tumor microenvironment, and genetic mutations such as translocation, or amplification. We have investigated the expression of PD-1, PD-L1, and tumor infiltrating lymphocytes (TIL) in 16 cases of SFT/HPC by immunohistochemistry. Kaplan-Meier method and log-rank/Wilcoxon tests were used to analyze the relationship between their expression with overall survival (OS), progression free survival (PFS), metastasis free survival (MFS), and time to treatment failure (TTF; metastasis or death). Additionally, we have analyzed amplification of PD-L1 gene by FISH, translocation between promotor region of CIITA and PD-L1 by PCR, and mutation in 3’-UTR by immunohistochemistry with antibody recognizes C-terminus (clone; SP-142) of PD-L1. PD-L1 was expressed in most of tumor cells. The intensity of PD-L1 expression was negatively associated with MFS (p=0.04), and diffuse pattern of PD-L1 expression showed trends towards shorter TTF compared with partial expression (p=0.08). Notably, with the combination analysis of PD-L1 and CD8(+) TIL, the diffuse PD-L1 expression with less CD8(+) was significantly associated with shorter TTF (p=0.005). However, there was no significant relevance between the expression of those immune-checkpoint molecules and OS or PFS. Although neither amplification of PD-L1 gene, 9p24.1, nor translocation between CITTA and PD-L1 were observed, difference in immunohistochemistry with two different anti-bodies was observed. In intracranial SFTs/HPCs, tumor immunity mechanism associated with PD-1/PD-L1 may play an important role in their extracranial metastases, and mutation in 3’-UTR may be a cause of PD-L1 activation in SFT/HPC.

scholarly journals Crosstalk Between the Tumor Microenvironment and Cancer Cells: A Promising Predictive Biomarker for Immune Checkpoint Inhibitors

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaoying Li ◽  
Yueyao Yang ◽  
Qian Huang ◽  
Yu Deng ◽  
Fukun Guo ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Small Proportion ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Cell Populations ◽  
Functional Interaction

Immune checkpoint inhibitors (ICIs) have changed the landscape of cancer treatment and are emerging as promising curative treatments in different type of cancers. However, only a small proportion of patients have benefited from ICIs and there is an urgent need to find robust biomarkers for individualized immunotherapy and to explore the causes of immunotherapy resistance. In this article, we review the roles of immune cells in the tumor microenvironment (TME) and discuss the effects of ICIs on these cell populations. We discuss the potential of the functional interaction between the TME and cancer cells as a predictive biomarker for ICIs. Furthermore, we outline the potential personalized strategies to improve the effectiveness of ICIs with precision.

Therapeutic checkpoint targets: Evaluation of co-expression profiles in individual tumor and immune cells in the tumor microenvironment of FFPE tissue.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 176-176
Author(s):  
Annelies Laeremans ◽  
Na Li ◽  
Jeff Kim ◽  
Xiao-Jun Ma ◽  
Emily Park
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Expression Profiles ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Durable Response

176 Background: Interactions between tumor and immune cells in the tumor microenvironment (TME) play a key role in tumor progression and treatment response with accumulating evidence indicating a crucial role for tumor infiltrating immune cells. Although infiltrating cytotoxic T lymphocytes (CTLs) have been correlated with improved clinical outcome, they are ineffective in eradicating tumors due to their inhibition by immune checkpoint molecules. Immune checkpoint inhibitors have demonstrated therapeutic efficacy and durable response for several tumor types including non-small cell lung cancer (NSCLC). However, the majority of patients are resistant or relapse after initial response. Characterizing the TME for checkpoint expression with single-cell and spatial resolution can provide critical insight into new immunotherapeutic strategies and identify new predictive biomarkers for stratifying and identifying patients most likely to benefit from immunotherapy including PD-1/PD-L1 immune checkpoint blockade. Methods: Using RNAscope in situ hybridization, we evaluated in situ co-expression profiles of therapeutic checkpoint targets at single-cell level in the TME of 56 archived NSCLC FFPE tissues. Results: Checkpoint molecules including PD1, PD-L1, PD-L2, TIM3, LAG3, CTLA-4 and GITR were visualized in a highly specific and sensitive manner in individual cells within tissue morphological context. Multiple checkpoint molecules were detected in the same immune environment, especially in highly inflamed tumors. In addition to PD-L1, tumor cell-intrinsic expression of PD1, TIM3, LAG3, and PD-L2 was observed in a subset of samples. Furthermore, co-expression of therapeutic checkpoint targets including PD1, LAG3, and TIM3 was observed in infiltrating immune cells and tumor cells. Conclusions: Single-cell co-expression profiles of checkpoint molecules could shed light on how cancer cells evade the host immune surveillance and develop resistance against checkpoint blockades. Also, they could reveal valuable insights into combinatorial therapies for checkpoint markers co-expressed by the patient’s immune cells in the TME.

scholarly journals Therapeutic Strategies for Overcoming Immunotherapy Resistance Mediated by Immunosuppressive Factors of the Glioblastoma Microenvironment

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1960
Author(s):  
Tsubasa Miyazaki ◽  
Eiichi Ishikawa ◽  
Narushi Sugii ◽  
Masahide Matsuda
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Malignant Tumors ◽  
Suppressor Cells ◽  
Treatment Resistance ◽  
Glioma Initiating Cells ◽  
Programmed Cell Death 1 ◽  
Tumor Immune Microenvironment ◽  
Immunosuppressive Tumor Microenvironment ◽  
Immunosuppressive Cells

Various mechanisms of treatment resistance have been reported for glioblastoma (GBM) and other tumors. Resistance to immunotherapy in GBM patients may be caused by acquisition of immunosuppressive ability by tumor cells and an altered tumor microenvironment. Although novel strategies using an immune-checkpoint inhibitor (ICI), such as anti-programmed cell death-1 antibody, have been clinically proven to be effective in many types of malignant tumors, such strategies may be insufficient to prevent regrowth in recurrent GBM. The main cause of GBM recurrence may be the existence of an immunosuppressive tumor microenvironment involving immunosuppressive cytokines, extracellular vesicles, chemokines produced by glioma and glioma-initiating cells, immunosuppressive cells, etc. Among these, recent research has paid attention to various immunosuppressive cells—including M2-type macrophages and myeloid-derived suppressor cells—that cause immunosuppression in GBM microenvironments. Here, we review the epidemiological features, tumor immune microenvironment, and associations between the expression of immune checkpoint molecules and the prognosis of GBM. We also reviewed various ongoing or future immunotherapies for GBM. Various strategies, such as a combination of ICI therapies, might overcome these immunosuppressive mechanisms in the GBM microenvironment.

scholarly journals Germinal BRCA-mutation significance in the tumor microenvironment formation Efficacy of PARP inhibition in late-line therapy of metastatic castration-resistant prostate cancer

2021 ◽  
Vol 17 (3) ◽  
pp. 85-94
Author(s):  
A. I. Stukan ◽  
A. Yu. Goryainova ◽  
N. A. Riger ◽  
S. V. Sharov ◽  
A. S. Shatokhina ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
T Lymphocytes ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Parp Inhibitors ◽  
Mutational Load ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Line Therapy

Metastatic castration-resistant prostate cancer is a difficult problem for a clinical oncologist. In addition, mutations in genes of homologous DNA recombination, including BRCA1/2, suggest an aggressive behavior and therapy resistance. Treatment options for such patients were significantly limited until new drugs - PARP inhibitors have been registered. Nevertheless, there is evidence that BRCA1/2 gene mutations are associated with increased mutational load, neoepitopes formation, increased number of tumor-infiltrating lymphocytes and a response to the immune response checkpoints blockade. Studies have shown that BRCA2-mutated prostate cancer demonstrates high level of immune cells infiltration compared to tumors without mutation, in particular with respect to CD4+, CD8+ and FOXP3+ T-lymphocytes. It should be noted that studies have shown a tendency of CD8+ T-lymphocytes/FOXP3+ T-cells ratio decreasing in BRCA2-mutated tumors. Thus, the mutational status of BRCA2 presumably forms the immune phenotype of prostate cancer with an increase of intratumoral immune cells, but with immunosuppressive properties. At the same time, the use of immune checkpoint blockers in advanced prostate cancer has been unsuccessful in terms of overall survival. Despite the fact that immune checkpoint blocker's efficacy is often associated with a high intracellular CD4+ and CD8+ T lymphocytes, their presence is clearly insufficient for response. Studies showed that PARP inhibitors effect tumor microenvironment significantly. Anti-PD-1/PD-L1 combination with PARP inhibitors is being actively studied due to their properties of modulating the tumor microenvironment. Thus, future immunooncological strategies for primary prostate cancer therapy may include not only an increase in mutational load, but also an impact on the immunosuppressive microenvironment. The article presents clinical cases of 3 brothers, carriers of the germinal BRCA2 c.9371A>T mutation, suffering from prostate cancer with a burdened family history. The disease development under standard therapies was studied and markers of the tumor microenvironment were immunohistochemically evaluated. PARP inhibitor Olaparib efficacy in prostate cancer of older brother in late-line therapy for metastatic castration-resistant disease was analyzed.

scholarly journals RNF208, an estrogen-inducible E3 ligase, targets soluble Vimentin to suppress metastasis in triple-negative breast cancers

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Kyoungwha Pang ◽  
Jinah Park ◽  
Sung Gwe Ahn ◽  
Jihee Lee ◽  
Yuna Park ◽  
...  
Keyword(s):  
Estrogen Receptor Alpha ◽  
Triple Negative ◽  
Ring Finger ◽  
Proteasomal Degradation ◽  
Degradation Pathway ◽  
Tumor Formation ◽  
Negative Regulator ◽  
Soluble Form ◽  
Dependent Manner ◽  
Breast Cancers

AbstractThe development of triple-negative breast cancer (TNBC) negatively impacts both quality of life and survival in a high percentage of patients. Here, we show that RING finger protein 208 (RNF208) decreases the stability of soluble Vimentin protein through a polyubiquitin-mediated proteasomal degradation pathway, thereby suppressing metastasis of TNBC cells. RNF208 was significantly lower in TNBC than the luminal type, and low expression of RNF208 was strongly associated with poor clinical outcomes. Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner. Overexpression of RNF208 suppresses tumor formation and lung metastasis of TNBC cells. Mechanistically, RNF208 specifically polyubiquitinated the Lys97 residue within the head domain of Vimentin through interaction with the Ser39 residue of phosphorylated Vimentin, which exists as a soluble form, eventually facilitating proteasomal degradation of Vimentin. Collectively, our findings define RNF208 as a negative regulator of soluble Vimentin and a prognostic biomarker for TNBC cells.

scholarly journals Requirements of Multiple Domains of SLI-1, aCaenorhabditis elegansHomologue of c-Cbl, and an Inhibitory Tyrosine in LET-23 in Regulating Vulval Differentiation

2000 ◽  
Vol 11 (11) ◽  
pp. 4019-4031 ◽  
Author(s):  
Charles H. Yoon ◽  
Chieh Chang ◽  
Neil A. Hopper ◽  
Giovanni M. Lesa ◽  
Paul W. Sternberg
Keyword(s):  
Calcium Binding ◽  
Ring Finger ◽  
Growth Factor Receptor ◽  
Chimeric Protein ◽  
Sh2 Domain ◽  
Negative Regulator ◽  
Functional Assay ◽  
Ring Finger Domain ◽  
C Terminus ◽  
Ras Activation

SLI-1, a Caenorhabditis elegans homologue of the proto-oncogene product c-Cbl, is a negative regulator of LET-23-mediated vulval differentiation. Lack of SLI-1 activity can compensate for decreased function of the LET-23 epidermal growth factor receptor, the SEM-5 adaptor, but not the LET-60 RAS, suggesting that SLI-1 acts before RAS activation. SLI-1 and c-Cbl comprise an N-terminal region (termed SLI-1:N/Cbl-N, containing a four-helix bundle, an EF hand calcium-binding domain, and a divergent SH2 domain) followed by a RING finger domain and a proline-rich C-terminus. In a transgenic functional assay, the proline-rich C-terminal domain is not essential for sli-1(+) function. A protein lacking the SH2 and RING finger domains has no activity, but a chimeric protein with the SH2 and RING finger domains of SLI-1 replaced by the equivalent domains of c-Cbl has activity. The RING finger domain of c-Cbl has been shown recently to enhance ubiquitination of active RTKs by acting as an E3 ubiquitin–protein ligase. We find that the RING finger domain of SLI-1 is partially dispensable. Further, we identify an inhibitory tyrosine of LET-23 requiring sli-1(+) for its effects: removal of this tyrosine closely mimics the loss ofsli-1 but not of another negative regulator,ark-1. Thus, we suggest that this inhibitory tyrosine mediates its effects through SLI-1, which in turn inhibits signaling upstream of LET-60 RAS in a manner not wholly dependent on the ubiquitin–ligase domain.

scholarly journals Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma

2022 ◽  
Vol 11 ◽  
Author(s):  
Saket Jain ◽  
Eric J. Chalif ◽  
Manish K. Aghi
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Randomized Clinical Trials ◽  
Neutralizing Antibody ◽  
Tumor Vasculature ◽  
Tumor Evolution ◽  
Therapeutic Modalities ◽  
Angiogenic Therapy ◽  
T Cell Infiltration ◽  
Immunosuppressive Microenvironment

Glioblastoma is the most aggressive brain tumor with a median survival ranging from 6.2 to 16.7 months. The complex interactions between the tumor and the cells of tumor microenvironment leads to tumor evolution which ultimately results in treatment failure. Immunotherapy has shown great potential in the treatment of solid tumors but has been less effective in treating glioblastoma. Failure of immunotherapy in glioblastoma has been attributed to low T-cell infiltration in glioblastoma and dysfunction of the T-cells that are present in the glioblastoma microenvironment. Recent advances in single-cell sequencing have increased our understanding of the transcriptional changes in the tumor microenvironment pre and post-treatment. Another treatment modality targeting the tumor microenvironment that has failed in glioblastoma has been anti-angiogenic therapy such as the VEGF neutralizing antibody bevacizumab, which did not improve survival in randomized clinical trials. Interestingly, the immunosuppressed microenvironment and abnormal vasculature of glioblastoma interact in ways that suggest the potential for synergy between these two therapeutic modalities that have failed individually. Abnormal tumor vasculature has been associated with immune evasion and the creation of an immunosuppressive microenvironment, suggesting that inhibiting pro-angiogenic factors like VEGF can increase infiltration of effector immune cells into the tumor microenvironment. Remodeling of the tumor vasculature by inhibiting VEGFR2 has also been shown to improve the efficacy of PDL1 cancer immunotherapy in mouse models of different cancers. In this review, we discuss the recent developments in our understanding of the glioblastoma tumor microenvironment specially the tumor vasculature and its interactions with the immune cells, and opportunities to target these interactions therapeutically. Combining anti-angiogenic and immunotherapy in glioblastoma has the potential to unlock these therapeutic modalities and impact the survival of patients with this devastating cancer.

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