scholarly journals Risk Signature Related to Immunotherapy Reaction of Hepatocellular Carcinoma Based on the Immune-Related Genes Associated With CD8+ T Cell Infiltration

2021 ◽  
Vol 8 ◽  
Author(s):  
Yiping Zou ◽  
Zhihong Chen ◽  
Hongwei Han ◽  
Shiye Ruan ◽  
Liang Jin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Risk Group ◽  
Checkpoint Inhibitors ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Immune Related Genes

Background: Hepatocellular carcinoma (HCC) is the most common histological type of liver cancer, with an unsatisfactory long-term survival rate. Despite immune checkpoint inhibitors for HCC have got glories in recent clinical trials, the relatively low response rate is still a thorny problem. Therefore, there is an urgent need to screen biomarkers of HCC to predict the prognosis and efficacy of immunotherapy.Methods: Gene expression profiles of HCC were retrieved from TCGA, GEO, and ICGC databases while the immune-related genes (IRGs) were retrieved from the ImmPort database. CIBERSORT and WGCNA algorithms were combined to identify the gene module most related to CD8+ T cells in the GEO cohort. Subsequently, the genes in hub modules were subjected to univariate, LASSO, and multivariate Cox regression analyses in the TCGA cohort to develop a risk signature. Afterward, the accuracy of the risk signature was validated by the ICGC cohort, and its relationships with CD8+ T cell infiltration and PDL1 expression were explored.Results: Nine IRGs were finally incorporated into a risk signature. Patients in the high-risk group had a poorer prognosis than those in the low-risk group. Confirmed by TCGA and ICGC cohorts, the risk signature possessed a relatively high accuracy. Additionally, the risk signature was demonstrated as an independent prognostic factor and closely related to the CD8+ T cell infiltration and PDL1 expression.Conclusion: A risk signature was constructed to predict the prognosis of HCC patients and detect patients who may have a higher positive response rate to immune checkpoint inhibitors.

scholarly journals A Novel Nine-lncRNA Risk Signature Correlates With Immunotherapy in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Ye Nie ◽  
Jianhui Li ◽  
Wenlong Wu ◽  
Dongnan Guo ◽  
Xinjun Lei ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Risk Group ◽  
Checkpoint Inhibitors ◽  
Risk Groups ◽  
Low Risk ◽  
Significant Difference ◽  
Checkpoint Genes

BackgroundHepatocellular carcinoma is one of the most common malignant tumors with a very high mortality rate. The emergence of immunotherapy has brought hope for the cure of hepatocellular carcinoma. Only a small number of patients respond to immune checkpoint inhibitors, and ferroptosis and tertiary lymphoid structure contribute to the increased response rate of immune checkpoint inhibitors; thus, we first need to identify those who are sensitive to immunotherapy and then develop different methods to improve sensitivity for different groups.MethodsThe sequencing data of hepatocellular carcinoma from The Cancer Genome Atlas and Gene Expression Omnibus was downloaded to identify the immune-related long non-coding RNAs (lncRNAs). LncRNAs related to survival data were screened out, and a risk signature was established using Cox proportional hazard regression model. R software was used to calculate the riskScore of each patient, and the patients were divided into high- and low-risk groups. The prognostic value of riskScore and its application in clinical chemotherapeutic drugs were confirmed. The relationship between riskScore and immune checkpoint genes, ferroptosis genes, and genes related to tertiary lymphoid structure formation was analyzed by Spearman method. TIMER, CIBERSORT, ssGSEA, and ImmuCellAI were used to evaluate the relative number of lymphocytes in tumor. The Wilcoxon signed-rank test confirmed differences in immunophenoscore between the high- and low-risk groups.ResultsData analysis revealed that our signature could well predict the 1-, 2-, 3-, and 5-year survival rates of hepatocellular carcinoma and to predict susceptible populations with Sorafenib. The risk signature were significantly correlated with immune checkpoint genes, ferroptosis genes, and tertiary lymphoid structure-forming genes, and predicted tumor-infiltrating lymphocyte status. There was a significant difference in IPS scores between the low-risk group and the high-risk group, while the low-risk group had higher scores.ConclusionThe riskScore obtained from an immune-related lncRNA signature could successfully predict the survival time and reflect the efficacy of immune checkpoint inhibitors. More importantly, it is possible to select different treatments for different hepatocellular carcinoma patients that increase the response rate of immune checkpoint inhibitors and will help improve the individualized treatment of hepatocellular carcinoma.

scholarly journals A novel tumor doubling time-related immune gene signature for prognosis prediction in hepatocellular carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Genhao Zhang ◽  
Lisa Su ◽  
Xianping Lv ◽  
Qiankun Yang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Doubling Time ◽  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Gene Signature ◽  
Tumor Doubling Time ◽  
Prognosis Prediction ◽  
Immune Related Genes

Abstract Background Hepatocellular carcinoma (HCC) has become a global health issue of wide concern due to its high prevalence and poor therapeutic efficacy. Both tumor doubling time (TDT) and immune status are closely related to the prognosis of HCC patients. However, the association between TDT-related genes (TDTRGs) and immune-related genes (IRGs) and the value of their combination in predicting the prognosis of HCC patients remains unclear. The current study aimed to discover reliable biomarkers for anticipating the future prognosis of HCC patients based on the relationship between TDTRGs and IRGs. Methods Tumor doubling time-related genes (TDTRGs) were acquired from GSE54236 by using Pearson correlation test and immune-related genes (IRGs) were available from ImmPort. Prognostic TDTRGs and IRGs in TCGA-LIHC dataset were determined to create a prognostic model by the LASSO-Cox regression and stepwise Cox regression analysis. International Cancer Genome Consortium (ICGC) and another cohort of individual clinical samples acted as external validations. Additionally, significant impacts of the signature on HCC immune microenvironment and reaction to immune checkpoint inhibitors were observed. Results Among the 68 overlapping genes identified as TDTRG and IRG, a total of 29 genes had significant prognostic relevance and were further selected by performing a LASSO-Cox regression model based on the minimum value of λ. Subsequently, a prognostic three-gene signature including HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), C-type lectin domain family 1 member B (CLEC1B), and Collectin sub-family member 12 (COLEC12) was finally identified by stepwise Cox proportional modeling. The signature exhibited superior accuracy in forecasting the survival outcomes of HCC patients in TCGA, ICGC and the independent clinical cohorts. Patients in high-risk subgroup had significantly increased levels of immune checkpoint molecules including PD-L1, CD276, CTLA4, CXCR4, IL1A, PD-L2, TGFB1, OX40 and CD137, and are therefore more sensitive to immune checkpoint inhibitors (ICIs) treatment. Finally, we first found that overexpression of CLEC1B inhibited the proliferation and migration ability of HuH7 cells. Conclusions In summary, the prognostic signature based on TDTRGs and IRGs could effectively help clinicians classify HCC patients for prognosis prediction and individualized immunotherapies.

CTLA4 and CD47 combinational therapy to extend survival in melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21025-e21025
Author(s):  
Anthony L. Schwartz ◽  
Pulak Nath ◽  
Elizabeth Lessey-Morillon ◽  
Lisa Ridnour ◽  
Michael Allgaeuer ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cell Activation ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Granzyme B ◽  
Suppressor Cells ◽  
Cell Infiltration

e21025 Background: Irradiation (IR) combined with chemotherapy is the post-surgical standard of care treatment for melanoma, but metastasis still results in high mortality rates. Immune checkpoint inhibitors such as cytotoxic T-lymphocyte antigen-4 (CTLA4) have proven effective for immunotherapy of melanoma. CTLA-4 is up-regulated post-T cell activation and blockade enhances tumor responses in immunocompetent rodents and humans. Trials suggest that combinations of immune checkpoint inhibitors are more efficacious than single agents, but tumors remain resistant. We are investigating CD47 blockade for the treatment of cancer. CD47 is frequently elevated in cancers and serves as an inhibitory receptor for thrombospondin-1 on immune cells in the tumor stroma. CD47 blockade on CD8 T or tumor cells significantly enhances immune-targeted tumor cell killing post-IR compared to IR alone. Here we explore the potential for antisense CD47 and anti-CTLA4 therapy alone or in combination with IR using a syngeneic mouse melanoma model. Methods: C57BL/6 mice were inoculated with 1x106B16F10 melanoma cells in the hind limb and treated with 10 Gy IR combined with CTLA4 blocking antibody, CD47 translational blocking morpholino, or the combination of CTLA4/CD47 therapies. Granzyme B along with CD4/CD8 T cell infiltration were examined in tumors. Histology was evaluated for CD3 and necrosis. Results: The combination of CD47/CTLA4 with IR significantly increased survival by 25% compared to IR/CTLA4 alone at 50 days. Granzyme B expression was significantly increased in IR mice with CTLA4/CD47 combination, which correlated with infiltration of CD8+ T cells and a concomitant decrease in Gr1+CD11b suppressor cells compared to controls. In non-IR tumors, histology revealed minimal necrosis, while all IR groups showed increased necrosis. Tumor IR in combination with CTLA4 or CD47 increased immune cell infiltration. However, the combination of IR with CTLA4/CD47 showed widespread necrosis. All groups treated with the CD47 exhibited focal hemorrhage, which was more extensive when combined with CTLA4. Conclusions: Results herein suggest IR combined CTLA4/CD47 checkpoint blockade provides a survival benefit by activating a beneficial adaptive immune response.

scholarly journals Poly-IC enhances the effectiveness of cancer immunotherapy by promoting T cell tumor infiltration

2020 ◽  
Vol 8 (2) ◽  
pp. e001224 ◽  
Author(s):  
Hussein Sultan ◽  
Juan Wu ◽  
Valentyna I Fesenkova ◽  
Aaron E Fan ◽  
Diane Addis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Cell Infiltration ◽  
Mouse Tumor ◽  
Type I ◽  
Antitumor Effects ◽  
Cell Therapies ◽  
T Cell Infiltration

BackgroundImmunotherapies, such as immune checkpoint inhibitors and adoptive cell therapies, have revolutionized cancer treatment and resulted in complete and durable responses in some patients. Unfortunately, most immunotherapy treated patients still fail to respond. Absence of T cell infiltration to the tumor site is one of the major obstacles limiting immunotherapy efficacy against solid tumors. Thus, the development of strategies that enhance T cell infiltration and broaden the antitumor efficacy of immunotherapies is greatly needed.MethodsWe used mouse tumor models, genetically deficient mice and vascular endothelial cells (VECs) to study the requirements for T cell infiltration into tumors.ResultsA specific formulation of poly-IC, containing poly-lysine and carboxymethylcellulose (PICLC) facilitated the traffic and infiltration of effector CD8 T cells into the tumors that reduced tumor growth. Surprisingly, intratumoral injection of PICLC was significantly less effective in inducing tumor T cell infiltration and controlling growth of tumors as compared with systemic (intravenous or intramuscular) administration. Systemically administered PICLC, but not poly-IC stimulated tumor VECs via the double-stranded RNA cytoplasmic sensor MDA5, resulting in enhanced adhesion molecule expression and the production of type I interferon (IFN-I) and T cell recruiting chemokines. Expression of IFNαβ receptor in VECs was necessary to obtain the antitumor effects by PICLC and IFN-I was found to directly stimulate the secretion of T cell recruiting chemokines by VECs indicating that this cytokine-chemokine regulatory axis is crucial for recruiting effector T cells into the tumor parenchyma. Unexpectedly, these effects of PICLC were mostly observed in tumors and not in normal tissues.ConclusionsThese findings have strong implications for the improvement of all types of T cell-based immunotherapies for solid cancers. We predict that systemic administration of PICLC will improve immune checkpoint inhibitor therapy, adoptive cell therapies and therapeutic cancer vaccines.

Cell proliferation as a biomarker for response to immune checkpoint inhibitors in PD-L1 negative renal cell carcinoma.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 62-62
Author(s):  
Sean T. Glenn ◽  
Sarabjot Pabla ◽  
Jason Zhu ◽  
Matthew Labriola ◽  
Rajan Gupta ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Reference Population ◽  
Rna Seq ◽  
The Mean ◽  
Immune Related Genes ◽  
Important Marker

62 Background: Cell proliferation is an important marker of survival in many tumors, and we hypothesized that this attribute could be related to response to immune checkpoint inhibitors (ICIs) in RCC. Previously we reported (SITC 2018) that moderately proliferative lung cancer have a much higher response rate than either poorly or highly proliferative tumors. Methods: 69 FFPE RCC tumor samples were evaluated by RNA-seq to measure transcript levels of 394 immune related genes. Cell proliferation was defined as the mean mRNA expression of 10 genes (BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, TOP2A) which was evaluated for association with ORR to ICIs by RECIST v1.1 criteria for both PD-L1 IHC positive and negative cases. Cell proliferation for each case was split into 3 tertiles of poorly ( < 33), moderately (33-66) and highly ( > 66) proliferative versus a reference population. Poorly and highly proliferative were grouped for comparison to moderately proliferative tumors. PD-L1 IHC was performed using DAKO 22C3 antibody and scored by FDA guidelines and considered positive if TPS ≥1% and negative if < 1%. Results: In our cohort of 69 patients, the overall ORR was 18.8. The majority, 91% of tumors were PD-L1 negative, with ORR of 14.8%, as opposed to ORR of 50% in PD-L1 positive cases. 62.2% of tumors were poorly proliferative, 8.7% were highly proliferative, and 29% were moderately proliferative. ORR in moderately proliferative tumors was 30% and 14.2% in poorly/highly proliferative tumors. In PD-L1 negative tumors the ORR in moderately proliferative tumors was 20% and 13% in poorly/highly proliferative tumors. For the 5 moderately proliferative, PD-L1 positive tumors, there were 2 PR and 1 CR, and in the 3 poorly/highly proliferative tumors there was 1 PR. Conclusions: Cell proliferation may play a crucial role in distinguishing RCC patients who may have a clinical benefit to ICI, including the important subgroup of PD-L1 negative tumors. Moderately proliferative tumors have a higher ORR than their poorly/highly counterparts.

scholarly journals MRI of tumor T cell infiltration in response to checkpoint inhibitor therapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000328 ◽  
Author(s):  
Xiaoyu Jiang ◽  
Stephanie Dudzinski ◽  
Kathryn E Beckermann ◽  
Kirsten Young ◽  
Eliot McKinley ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Cell Size ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Cell Infiltration ◽  
Response Criteria ◽  
Non Invasive ◽  
T Cell Infiltration

BackgroundImmune checkpoint inhibitors, the most widespread class of immunotherapies, have demonstrated unique response patterns that are not always adequately captured by traditional response criteria such as the Response Evaluation Criteria in Solid Tumors or even immune-specific response criteria. These response metrics rely on monitoring tumor growth, but an increase in tumor size and/or appearance after starting immunotherapy does not always represent tumor progression, but also can be a result of T cell infiltration and thus positive treatment response. Therefore, non-invasive and longitudinal monitoring of T cell infiltration are needed to assess the effects of immunotherapies such as checkpoint inhibitors. Here, we proposed an innovative concept that a sufficiently large influx of tumor infiltrating T cells, which have a smaller diameter than cancer cells, will change the diameter distribution and decrease the average size of cells within a volume to a degree that can be quantified by non-invasive MRI.MethodsWe validated our hypothesis by studying tumor response to combination immune-checkpoint blockade (ICB) of anti-PD-1 and anti-CTLA4 in a mouse model of colon adenocarcinoma (MC38). The response was monitored longitudinally using Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion (IMPULSED), a diffusion MRI-based method which has been previously shown to non-invasively map changes in intracellular structure and cell sizes with the spatial resolution of MRI, in cell cultures and in animal models. Tumors were collected for immunohistochemical and flow cytometry analyzes immediately after the last imaging session.ResultsImmunohistochemical analysis revealed that increased T cell infiltration of the tumors results in a decrease in mean cell size (eg, a 10% increase of CD3+ T cell fraction results a ~1 µm decrease in the mean cell size). IMPULSED showed that the ICB responders, mice with tumor volumes were less than 250 mm3 or had tumors with stable or decreased volumes, had significantly smaller mean cell sizes than both Control IgG-treated tumors and ICB non-responder tumors.ConclusionsIMPULSED-derived cell size could potentially serve as an imaging marker for differentiating responsive and non-responsive tumors after checkpoint inhibitor therapies, a current clinical challenge that is not solved by simply monitoring tumor growth.

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

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