Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4060-4060
Author(s):  
Ronan Joseph Kelly ◽  
Ali Hussainy Zaidi ◽  
Matthew A Smith ◽  
Ashten N Omstead ◽  
Juliann E Kosovec ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Immune Checkpoints ◽  
Immune Microenvironment ◽  
Qrt Pcr ◽  
Tumor Bearing ◽  
Post Radiation ◽  
The Impact

4060 Background: PD-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25%. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with CRT in earlier stage esophageal cancer may prevent metastatic disease in a greater proportion of patients. This study assessed the impact of CRT on the immune microenvironment and the expression patterns of multiple immune checkpoints to optimally design neoadjuvant clinical trials. Methods: To determine the effects of CRT on resected esophageal adenocarcinomas (EAC), we examined the immune microenvironment pre and post CRT using IHC, LCM followed by qRT-PCR, and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 sensitization, esophagojejunostomy were performed on rats to induce gastroduodenoesophageal reflux and EAC formation. First, tumor bearing animals were dosed with single fraction 13 Gy or 16 Gy radiation to determine safety, dose correlation, and PD-L1 sensitization using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual tumor bearing animals were determined using serial endoscopic biopsies at baseline, 1, 5 and 9 weeks post 16 Gy radiation. Results: The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including – TIM3, GITR, IDO1, LAG3, CD137, OX40 and KIR. The animal model results indicated PD-L1 upregulation is dose dependent and transiently elevated post radiation exposure. Conclusions: Collectively, these findings provide insights into the evolving immune landscape after CRT and have significant implications for future neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors. Currently, we are conducting a neoadjuvant trial assessing Nivolumab or Nivolumab/Ipilimumab in combination with CRT in stage II/III operable esophageal cancer.

scholarly journals A Systematic Review of the Tumor-Infiltrating CD8+ T-Cells/PD-L1 Axis in High-Grade Glial Tumors: Toward Personalized Immuno-Oncology

2021 ◽  
Vol 12 ◽  
Author(s):  
Mahdi Abdoli Shadbad ◽  
Zahra Asadzadeh ◽  
Negar Hosseinkhani ◽  
Afshin Derakhshani ◽  
Nazila Alizadeh ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Cancer Therapies ◽  
High Grade ◽  
Glial Tumors ◽  
Anti Cancer ◽  
The Impact

Based on preclinical findings, programmed death-ligand 1 (PD-L1) can substantially attenuate CD8+ T-cell-mediated anti-tumoral immune responses. However, clinical studies have reported controversial results regarding the significance of the tumor-infiltrating CD8+ T-cells/PD-L1 axis on the clinical picture and the response rate of patients with high-grade glial tumors to anti-cancer therapies. Herein, we conducted a systematic review according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements to clarify the clinical significance of the tumor-infiltrating CD8+ T-cells/PD-L1 axis and elucidate the impact of this axis on the response rate of affected patients to anti-cancer therapies. Indeed, a better understanding of the impact of this axis on the response rate of affected patients to anti-cancer therapies can provide valuable insights to address the futile response rate of immune checkpoint inhibitors in patients with high-grade glial tumors. For this purpose, we systematically searched Scopus, Web of Science, Embase, and PubMed to obtain peer-reviewed studies published before 1 January 2021. We have observed that PD-L1 overexpression can be associated with the inferior prognosis of glioblastoma patients who have not been exposed to chemo-radiotherapy. Besides, exposure to anti-cancer therapies, e.g., chemo-radiotherapy, can up-regulate inhibitory immune checkpoint molecules in tumor-infiltrating CD8+ T-cells. Therefore, unlike unexposed patients, increased tumor-infiltrating CD8+ T-cells in anti-cancer therapy-exposed tumoral tissues can be associated with the inferior prognosis of affected patients. Because various inhibitory immune checkpoints can regulate anti-tumoral immune responses, the single-cell sequencing of the cells residing in the tumor microenvironment can provide valuable insights into the expression patterns of inhibitory immune checkpoints in the tumor micromovement. Thus, administrating immune checkpoint inhibitors based on the data from the single-cell sequencing of these cells can increase patients’ response rates, decrease the risk of immune-related adverse events development, prevent immune-resistance development, and reduce the risk of tumor recurrence.

scholarly journals Immune-checkpoint engagement as predictive biomarkers in clear cell renal cell carcinoma and melanoma

2020 ◽  
Author(s):  
Lissete Sánchez-Magraner ◽  
James Miles ◽  
Claire Baker ◽  
Christopher J Applebee ◽  
Dae-Jin Lee ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Predictive Biomarkers ◽  
Immune Checkpoints ◽  
Ligand Interaction ◽  
Receptor Ligand ◽  
Programmed Death ◽  
Cell Cell

ABSTRACTMany cancers are termed immuno-evasive due to expression of immuno-modulatory ligands. Programmed death ligand-1 (PD-L1) and cluster of differentiation 80/86 (CD80/86) interact with their receptors, programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4), on tumour infiltrating leukocytes, thus eliciting immunosuppression. Immunotherapies aimed at blocking these interactions are revolutionising cancer treatments, albeit in an inadequately described patient subset.Our prognostic assay, utilising amplified two-site time-resolved Förster resonance energy transfer (iFRET), quantifies PD-1/ PD-L1 and CTLA-4/ CD80 cell-cell interactions in single cell assays and tumour biopsies. iFRET efficiencies demonstrate, in cell-cell engagement models, that receptor-ligand interactions are significantly lower with anti-PD-1 or anti-CTLA-4 blocking antibodies. In patient samples, iFRET detects immune-cell/tumour-cell interaction variance in different cancers. These results revealed inter-cancer, inter-patient and intra-tumoural heterogeneity of engaged immune-checkpoints, contradicting their ligand expression patterns. Exploiting spatio-temporal interactions of immune-checkpoint proteins defined biomarker functionality for determining whether checkpoint inhibitors are appropriate treatments.Statement of SignificanceQuantitative photophysics exploitation in determining immune-checkpoint engagement, as predictive biomarkers in cancers led to revealing inter-cancer, inter-patient and intra-tumoural heterogeneity of the engaged immune-checkpoints. This receptor-ligand interaction did not reflect simple expression patterns of these immuno-modulatory proteins. Our findings may affect immunotherapies aimed at blocking these intercellular interactions in patients.

scholarly journals Modelling of Immune Checkpoint Network Explains Synergistic Effects of Combined Immune Checkpoint Inhibitor Therapy and the Impact of Cytokines in Patient Response

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3600
Author(s):  
Maria Kondratova ◽  
Emmanuel Barillot ◽  
Andrei Zinovyev ◽  
Laurence Calzone
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Cell Biology ◽  
Checkpoint Inhibitors ◽  
Synergistic Effects ◽  
Experimental Studies ◽  
Immune Checkpoints ◽  
Interleukin 12 ◽  
Good Correspondence ◽  
The Impact

After the success of the new generation of immune therapies, immune checkpoint receptors have become one important center of attention of molecular oncologists. The initial success and hopes of anti-programmed cell death protein 1 (anti-PD1) and anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) therapies have shown some limitations since a majority of patients have continued to show resistance. Other immune checkpoints have raised some interest and are under investigation, such as T cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT), inducible T-cell costimulator (ICOS), and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), which appear as promising targets for immunotherapy. To explore their role and study possible synergetic effects of these different checkpoints, we have built a model of T cell receptor (TCR) regulation including not only PD1 and CTLA4, but also other well studied checkpoints (TIGIT, TIM3, lymphocyte activation gene 3 (LAG3), cluster of differentiation 226 (CD226), ICOS, and tumour necrosis factor receptors (TNFRs)) and simulated different aspects of T cell biology. Our model shows good correspondence with observations from available experimental studies of anti-PD1 and anti-CTLA4 therapies and suggest efficient combinations of immune checkpoint inhibitors (ICI). Among the possible candidates, TIGIT appears to be the most promising drug target in our model. The model predicts that signal transducer and activator of transcription 1 (STAT1)/STAT4-dependent pathways, activated by cytokines such as interleukin 12 (IL12) and interferon gamma (IFNG), could improve the effect of ICI therapy via upregulation of Tbet, suggesting that the effect of the cytokines related to STAT3/STAT1 activity is dependent on the balance between STAT1 and STAT3 downstream signalling.

scholarly journals The Impact of NOTCH Pathway Alteration on Tumor Microenvironment and Clinical Survival of Immune Checkpoint Inhibitors in NSCLC

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaohua Li ◽  
Yuntao Wang ◽  
Xuebing Li ◽  
Gang Feng ◽  
Sheng Hu ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Notch Signaling ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Immune Microenvironment ◽  
Mutation Status ◽  
Nsclc Patients ◽  
The Impact

The treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) has been proven to induce lasting tumor remission. Screening suitable populations for immunotherapy through predictive markers is an important approach to improving the clinical benefits of patients. Evidence has shown that there may be a close connection between NOTCH signaling and the tumor microenvironment (TME). Hence, we explored the impact of the mutation status of NOTCH signaling on the prognosis of NSCLC patients treated with immunotherapy with the aim to apply NSCLC immunotherapy to the greatest extent possible. We examined two clinical cohorts of NSCLC patients receiving ICIs (MSKCC and NG cohorts). The mutation and prognostic data of the ICI-treated cohort were used to evaluate the association between the mutation status of NOTCH signaling and prognosis following immunotherapy. The expression and mutation data of The Cancer Genome Atlas (TCGA)-NSCLC cohort were used to analyze the differences in the immune microenvironment under different NOTCH signaling mutation states. In the ICI-treated cohorts, the univariate and multivariate Cox regression analyses indicated that high-mutated NOTCH signaling could serve as an independent predictor of NSCLC patients receiving ICIs. Patients with high-mutated NOTCH signaling had significantly improved progression-free survival (PFS) (P = 0.03, HR = 0.69; MSKCC cohort) and prolonged overall survival (OS) (P = 0.004, HR = 0.34; NG cohort). Additionally, high-mutated NOTCH signaling was related to the inflammatory immune microenvironment, inflammatory expression profile, and enhanced immunogenicity. According to this study, high-mutated NOTCH signaling may serve as a biomarker for the prediction of the prognosis of NSCLC patients treated with ICIs. A series of prospective clinical studies and molecular mechanism explorations are still needed in the future.

Immune checkpoint and checkpoint inhibitors in hepatocellular carcinoma

2018 ◽  
Vol 1 (1) ◽  
pp. 28-32
Author(s):  
Piyawat Komolmit
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell Receptor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Receptor ◽  
Immune Checkpoints ◽  
Histocompatibility Complex

การรักษามะเร็งด้วยแนวความคิดของการกระตุ้นให้ภูมิต้านทานของร่างกายไปทำลายเซลล์มะเร็งนั้น ปัจจุบันได้รับการพิสูจน์ชัดว่าวิธีการนี้สามารถหยุดยั้งการแพร่กระจายของเซลล์มะเร็ง โดยไม่ก่อให้เกิดภาวะแทรกซ้อนทางปฏิกิริยาภูมิต้านทานต่ออวัยวะส่วนอื่นที่รุนแรง สามารถนำมาใช้ทางคลินิกได้ ยุคของการรักษามะเร็งกำลังเปลี่ยนจากยุคของยาเคมีบำบัดเข้าสู่การรักษาด้วยภูมิต้านทาน หรือ immunotherapy ยากลุ่ม Immune checkpoint inhibitors โดยเฉพาะ PD-1 กับ CTLA-4 inhibitors จะเข้ามามีบทบาทในการรักษามะเร็งตับในระยะเวลาอันใกล้ จำเป็นแพทย์จะต้องมีความรู้ความเข้าใจในพื้นฐานของ immune checkpoints และยาที่ไปยับยั้งโมเลกุลเหล่านี้ Figure 1 เมื่อ T cells รับรู้แอนทิเจนผ่านทาง TCR/MHC จะมีปฏิกิริยาระหว่าง co-receptors หรือ immune checkpoints กับ ligands บน APCs หรือ เซลล์มะเร็ง ทั้งแบบกระตุ้น (co-stimulation) หรือยับยั้ง (co-inhibition) TCR = T cell receptor, MHC = major histocompatibility complex

Immune Checkpoint Inhibitors in Patients with Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Case Report and Literature Review

2020 ◽  
Vol 20 (9) ◽  
pp. 720-727
Author(s):  
Jianguo Qiu ◽  
Wei Tang ◽  
Chengyou Du
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Immune Checkpoint ◽  
Graft Rejection ◽  
Checkpoint Inhibitors ◽  
Liver Graft ◽  
Immune Checkpoints ◽  
Term Survival ◽  
Liver Preservation ◽  
Programmed Death

Background: Immune checkpoint modulators, such as the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor, cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitor have been investigated with encouraging results for hepatocellular carcinoma (HCC). However, the safety of this strategy in patients with previous liver transplantation (LT) is not well studied. Objective: To explore the safety and feasibility of immune checkpoints inhibitors in recurrent and metastatic HCC patients on a background of LT. Methods: A case of recurrent, refractory, metastatic HCC after LT, where PD-1 inhibitor was initiated, was described and related literature was reviewed. Results: There was complete remission in lung metastases and the partial radiological response of metastatic retroperitoneal lymph node to the drug with no liver graft rejection after 13 cycles of PD- 1 inhibitor injection. PD-1inhibitor, at least in this patient, was verified to play an important role in controlling tumor progression and prolonging patient survival. Conclusions: This novel drug might be a useful method to allow doctors to guarantee a better chance for long-term survival in recurrent, metastatic HCC patients with the previous LT. However, it should be used with caution in allograft recipients due to the risk of acute graft rejection, further larger, prospective studies are needed to determine optimal immunomodulatory therapy to achieve optimal anti-tumor efficacy with transplant liver preservation.

scholarly journals From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2278
Author(s):  
Afshin Derakhshani ◽  
Zeinab Rostami ◽  
Hossein Safarpour ◽  
Mahdi Abdoli Shadbad ◽  
Niloufar Sadat Nourbakhsh ◽  
...  
Keyword(s):  
Single Cell ◽  
Signaling Pathways ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cancer Development ◽  
Immune Checkpoints ◽  
Single Cell Sequencing ◽  
Increased Risk

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

scholarly journals Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1949
Author(s):  
Yawen Dong ◽  
Jeffrey Sum Lung Wong ◽  
Ryohichi Sugimura ◽  
Ka-On Lam ◽  
Bryan Li ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Advanced Hcc ◽  
Oncogenic Pathways ◽  
Vegf Pathway ◽  
And Function ◽  
Endothelial Growth Factor

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.

scholarly journals miRNA Expression Characterizes Histological Subtypes and Metastasis in Penile Squamous Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1480
Author(s):  
Hiresh Ayoubian ◽  
Joana Heinzelmann ◽  
Sebastian Hölters ◽  
Oybek Khalmurzaev ◽  
Alexey Pryalukhin ◽  
...  
Keyword(s):  
Microarray Data ◽  
Expression Patterns ◽  
Hpv Infection ◽  
Differentially Expressed ◽  
Histological Subtypes ◽  
Specific Expression ◽  
Tissue Samples ◽  
Qrt Pcr ◽  
Differentially Expressed Mirnas ◽  
The Impact

Although microRNAs are described as promising biomarkers in many tumor types, little is known about their role in PSCC. Thus, we attempted to identify miRNAs involved in tumor development and metastasis in distinct histological subtypes considering the impact of HPV infection. In a first step, microarray analyses were performed on RNA from formalin-fixed, paraffin-embedded tumor (22), and normal (8) tissue samples. Microarray data were validated for selected miRNAs by qRT-PCR on an enlarged cohort, including 27 tumor and 18 normal tissues. We found 876 significantly differentially expressed miRNAs (p ≤ 0.01) between HPV-positive and HPV-negative tumor samples by microarray analysis. Although no significant differences were detected between normal and tumor tissue in the whole cohort, specific expression patterns occurred in distinct histological subtypes, such as HPV-negative usual PSCC (95 differentially expressed miRNAs, p ≤ 0.05) and HPV-positive basaloid/warty subtypes (247 differentially expressed miRNAs, p ≤ 0.05). Selected miRNAs were confirmed by qRT-PCR. Furthermore, microarray data revealed 118 miRNAs (p ≤ 0.01) that were significantly differentially expressed in metastatic versus non-metastatic usual PSCC. The lower expression levels for miR-137 and miR-328-3p in metastatic usual PSCC were validated by qRT-PCR. The results of this study confirmed that specific miRNAs could serve as potential diagnostic and prognostic markers in single PSCC subtypes and are associated with HPV-dependent pathways.

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