A RNA signature predicts outcomes in immune checkpoint blockade treated gastrointestinal cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14071-e14071
Author(s):  
Zhihao Lu ◽  
Huan Chen ◽  
Shuang Li ◽  
Xi Jiao ◽  
Lihong Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Gene Expression Pattern ◽  
Progression Free Survival ◽  
Gene Signature ◽  
Immune Checkpoint Blockade ◽  
Predictive Values ◽  
Gi Cancer ◽  
Mutation Burden

e14071 Background: Cancer therapy has been greatly revolutionized in recent years by the conceptual developments in the field of cancer immunology. Growing evidence support the utility of immune checkpoint inhibition (ICB) in gastrointestinal (GI) cancer. However, a central question lies in understanding how therapeutic responsiveness is predicted. Methods: To address this, we evaluated tumor FFPE specimens from 97 patients who received ICB treatment. All patients were randomly assigned into discovery (60%) and validation (40%) cohorts. Tumor RNA before ICB treatment was analyzed on a multiplex RNA immune oncology (RNA IO) profiling sequencing panel. Results: We show that four immune-related gene expression signatures were upregulated in responders versus non-responders in the discovery cohort. Three of the four signatures showed significant correlation with clinic response and disease control rates. However, two previously reported RNA signatures, PD-L1 expression and MMR status revealed less predictive values in GI cancers. More importantly, we identified that higher levels of a 19-gene signature were remarkably associated with favorable overall survival (OS) and progression-free survival (PFS) when compared to patients with lower levels of signature in both the discovery and validation cohorts. Of note, a joint biomarker of tumor mutation burden (TMB) and the 19-gene signature may better stratify responders from non-responders in GI cancer patients. Conclusions: Our data provide evidence that a responsive feature, defined by a multi-gene expression pattern across different GI cancer types, can be obtained via a RNA quantitative strategy and may be explored as a future pan-cancer biomarker.

scholarly journals Treatment with therapeutic anticoagulation is not associated with immunotherapy response in advanced cancer patients

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Paul Johannet ◽  
Amelia Sawyers ◽  
Nicholas Gulati ◽  
Douglas Donnelly ◽  
Samuel Kozloff ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Advanced Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Coagulation Cascade ◽  
Advanced Cancer Patients ◽  
Clinical Endpoints

Abstract Background Recent preclinical data suggest that there may be therapeutic synergy between immune checkpoint blockade and inhibition of the coagulation cascade. Here, we investigate whether patients who received immune checkpoint inhibitors (ICI) and were on concomitant anticoagulation (AC) experienced better treatment outcomes than individuals not on AC.Affiliation: Kindly confirm if corresponding authors affiliation is identified correctly.The corresponding author's affiliation is correct. Methods We studied a cohort of 728 advanced cancer patients who received 948 lines of ICI at NYU (2010–2020). Patients were classified based on whether they did (n = 120) or did not (n = 828) receive therapeutic AC at any point during their treatment with ICI. We investigated the relationship between AC status and multiple clinical endpoints including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of bleeding complications.Affiliations: Journal instruction requires a country for affiliations; however, this is missing in affiliations 1 to 5. Please verify if the provided country is correct and amend if necessary.The country is correct for all affiliations (1 - 5). Results Treatment with AC was not associated with significantly different BOR (P = 0.80), ORR (P =0.60), DCR (P =0.77), PFS (P = 0.59), or OS (P =0.64). Patients who received AC were significantly more likely to suffer a major or clinically relevant minor bleed (P = 0.05). Conclusion AC does not appear to impact the activity or efficacy of ICI in advanced cancer patients. On the basis of our findings, we caution that there is insufficient evidence to support prospectively evaluating the combination of AC and immunotherapy.

scholarly journals Tumor copy-number alterations predict response to immune-checkpoint-blockade in gastrointestinal cancer

2020 ◽  
Vol 8 (2) ◽  
pp. e000374 ◽  
Author(s):  
Zhihao Lu ◽  
Huan Chen ◽  
Shuang Li ◽  
Jifang Gong ◽  
Jian Li ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Copy Number ◽  
Validation Cohort ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Copy Number Alterations ◽  
Gi Cancer

BackgroundDespite the great achievements made in immune-checkpoint-blockade (ICB) in cancer therapy, there are no effective predictive biomarkers in gastrointestinal (GI) cancer.MethodsThis study included 93 metastatic GI patients treated with ICBs. The first cohort comprising 73 GI cancer patients were randomly assigned into discovery (n=44) and validation (n=29) cohorts. Comprehensive genomic profiling was performed on all samples to determine tumor mutational burden (TMB) and copy-number alterations (CNAs). A subset of samples was collected for RNA immune oncology (IO) panel sequencing, microsatellite instability (MSI)/mismatch repair and program death ligand 1 (PD-L1) expression evaluation. In addition, 20 gastric cancer (GC) patients were recruited as the second validation cohort.ResultsIn the first cohort of 73 GI cancer patients, a lower burden of CNA was observed in patients with durable clinical benefit (DCB). In both the discovery (n=44) and validation (n=29) subsets, lower burden of CNA was associated with an improved clinical benefit and better overall survival (OS). Efficacy also correlated with a higher TMB. Of note, a combinatorial biomarker of TMB and CNA may better stratify DCB patients from ICB treatment, which was further confirmed in the second validation cohort of 20 GC patients. Finally, patients with lower burden of CNA revealed increased immune signatures in our cohort and The Cancer Genome Atlas data sets as well.ConclusionsOur results suggest that the burden of CNA may have superior predictive value compared with other signatures, including PD-L1, MSI and TMB. The joint biomarker of CNA burden and TMB may better stratify DCB patients, thereby providing a rational choice for GI patients treated with ICBs.

scholarly journals Role of tumor gene mutations in treatment response to immune checkpoint blockades

2019 ◽  
Vol 2 (2) ◽  
pp. 100-109 ◽  
Author(s):  
Manni Wang ◽  
Liu Yu ◽  
Xiawei Wei ◽  
Yuquan Wei
Keyword(s):  
Gene Expression ◽  
Treatment Response ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Gene Mutations ◽  
Immune Checkpoint Blockade ◽  
Recent Developments ◽  
Tumor Gene

AbstractEarly studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment, with later studies applying immune checkpoint blockade (ICB) in treatment of various malignancies. Despite the encouraging efficacy of ICBs in a substantial subset of cancer patients, the treatment response varies. Gene mutations of both tumor cells and immune cells in the tumor microenvironment have recently been identified as potential predictors of the ICB response. Recent developments in gene expression profiling of tumors have allowed identification of a panel of mutated genes that may affect tumor cell response to ICB treatment. In this review, we discuss the association of the ICB response with gene expression and mutation profiles in tumor cells, which it is hoped will help to optimize the clinical application of ICBs in cancer patients.

LAG-3 expression on peripheral blood cells identifies patients with poorer outcomes after immune checkpoint blockade

2021 ◽  
Vol 13 (608) ◽  
pp. eabf5107
Author(s):  
Ronglai Shen ◽  
Michael A. Postow ◽  
Matthew Adamow ◽  
Arshi Arora ◽  
Margaret Hannum ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Peripheral Blood ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Clinical Activity ◽  
Multiparametric Flow Cytometry ◽  
Mutation Burden ◽  
Blocking Antibodies

Immune checkpoint blocking antibodies are a cornerstone in cancer treatment; however, they benefit only a subset of patients and biomarkers to guide immune checkpoint blockade (ICB) treatment choices are lacking. We designed this study to identify blood-based correlates of clinical outcome in ICB-treated patients. We performed immune profiling of 188 ICB-treated patients with melanoma using multiparametric flow cytometry to characterize immune cells in pretreatment peripheral blood. A supervised statistical learning approach was applied to a discovery cohort to classify phenotypes and determine their association with survival and treatment response. We identified three distinct immune phenotypes (immunotypes), defined in part by the presence of a LAG-3+CD8+ T cell population. Patients with melanoma with a LAG+ immunotype had poorer outcomes after ICB with a median survival of 22.2 months compared to 75.8 months for those with the LAG− immunotype (P = 0.031). An independent cohort of 94 ICB-treated patients with urothelial carcinoma was used for validation where LAG+ immunotype was significantly associated with response (P = 0.007), survival (P < 0.001), and progression-free survival (P = 0.004). Multivariate Cox regression and stratified analyses further showed that the LAG+ immunotype was an independent marker of outcome when compared to known clinical prognostic markers and previously described markers for the clinical activity of ICB, PD-L1, and tumor mutation burden. The pretreatment peripheral blood LAG+ immunotype detects patients who are less likely to benefit from ICB and suggests a strategy for identifying actionable immune targets for further investigation.

scholarly journals Response to FEC Chemotherapy and Oncolytic HSV-1 Is Associated with Macrophage Polarization and Increased Expression of S100A8/A9 in Triple Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5590
Author(s):  
Alyssa Vito ◽  
Nader El-Sayes ◽  
Omar Salem ◽  
Yonghong Wan ◽  
Karen L. Mossman
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Macrophage Polarization ◽  
Gene Signature ◽  
Immune Checkpoint Blockade ◽  
Differential Gene ◽  
Microarray Analyses ◽  
Tumor Cell Killing

The era of immunotherapy has seen an insurgence of novel therapies driving oncologic research and the clinical management of the disease. We have previously reported that a combination of chemotherapy (FEC) and oncolytic virotherapy (oHSV-1) can be used to sensitize otherwise non-responsive tumors to immune checkpoint blockade and that tumor-infiltrating B cells are required for the efficacy of our therapeutic regimen in a murine model of triple-negative breast cancer. In the studies herein, we have performed gene expression profiling using microarray analyses and have investigated the differential gene expression between tumors treated with FEC + oHSV-1 versus untreated tumors. In this work, we uncovered a therapeutically driven switch of the myeloid phenotype and a gene signature driving increased tumor cell killing.

scholarly journals 700 Increasing MHC-I expression to potentiate immune checkpoint blockade therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A728-A728
Author(s):  
Shengqing Gu ◽  
Wubing Zhang ◽  
Xiaoqing Wang ◽  
Peng Jiang ◽  
Nicole Traugh ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Mhc I ◽  
Expression Signature ◽  
Smac Mimetics ◽  
Smac Mimetic

BackgroundCancer immunotherapy, especially immune checkpoint blockade (ICB) therapy, is leading to a paradigm shift in cancer treatment, as a small percentage of cancer patients have obtained durable remission following ICB treatment. Successful ICB responses rely on cancer cells presenting antigens to the cell surface via the major histocompatibility complex (MHC), which activates antigen-specific T-lymphocytes to kill cancer cells. Type-I MHC (MHC-I) is wildly expressed in all cell types and mediates the interaction with cytotoxic CD8 T cells. However, over 65% of cancer patients are estimated to show defects in MHC-I-mediated antigen presentation, including downregulation of its expression that can lead to primary or acquired resistance to ICB therapy, and therapeutic strategies to effectively restore or boost MHC-I are limited.MethodsHere, we employed a CRISPR screening approach with dual-marker FACS sorting to identify factors that decouple the regulation of MHC-I and PD-L1. The experimentally validated target was used to generate a KO differential expression signature. Using this signature, we analyzed transcriptome data from drug perturbation studies to identify drugs that regulate MHC-I but not PD-L1. Finally, we validated the effect of the identified drug to enhance ICB response in a T-cell-dependent manner in vivo.ResultsCRISPR screens identified TRAF3, a suppressor of the NF-κB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified SMAC mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T-cell-dependent killing, and adds to ICB efficacy. However, in cancer cells with high NF-κB activity, the effect of birinapant on MHC-I is weak, indicating context-dependent MHC-I regulation.ConclusionsIn summary, Traf3 deletion specifically upregulates MHC-I without inducing PD-L1 in response to various cytokines and sensitizes cancer cells to T-cell-driven cytotoxicity. The SMAC mimetic birinapant phenocopies Traf3-knockout and sensitizes MHC-I-low melanoma to ICB therapy. Further studies are needed to elucidate the context-dependencies of MHC-I regulation. Our findings provide preclinical rationale for treating some tumors expressing low MHC-I with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy.AcknowledgementsThis study was supported by grants from the NIH (R01CA234018 to XSL, R01AI137337 to BEG, P50CA101942-12 and P50CA206963 to GJF), Breast Cancer Research Foundation (BCRF-19-100 to XSL), Burroughs Wellcome Career Award in Medical Sciences (to BEG), and Sara Elizabeth O'Brien Trust Fellowship (to SG).We thank Drs. Kai Wucherpfennig and Deng Pan for their insightful suggestions on this study.Ethics ApprovalAll mice were housed in standard cage in Dana-Farber Cancer Institute Animal Resources Facility (ARF). All animal procedures were carried out under the ARF Institutional Animal Care and Use Committee (IACUC) protocol and were in accordance with the IACUC standards for the welfare of animals.

scholarly journals Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Zhihao Lu ◽  
Huan Chen ◽  
Xi Jiao ◽  
Yujiao Wang ◽  
Lijia Wu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Gene Mutations ◽  
Human Leukocyte ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cancer Center ◽  
Driver Gene ◽  
Evolutionary Divergence ◽  
Rna Profiling ◽  
Gi Cancer

Abstract Background The human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious disease and cancer. However, the clinical relevance of germline HLA-mediated immunity in gastrointestinal (GI) cancer remains elusive. Methods This study retrospectively analyzed the genomic profiling data from 84 metastatic GI cancer patients treated with immune checkpoint blockade (ICB) recruited from Peking University Cancer Hospital (PUCH). A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was employed as the validation cohort. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood samples from all patients. Tumor tissues from 76 patients were subjected to WES analysis and immune oncology-related RNA profiling. We studied the associations of two parameters of germline HLA as heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) with the clinical outcomes of patients in both cohorts. Results Our data showed that neither HLA heterozygosity nor HED at the HLA-A/HLA-C locus correlated with the overall survival (OS) in the PUCH cohort. Interestingly, in both the PUCH and MSK GI cohorts, patients with high HLA-B HED showed a better OS compared with low HLA-B HED subgroup. Of note, a combinatorial biomarker of HLA-B HED and tumor mutational burden (TMB) may better stratify potential responders. Furthermore, patients with high HLA-B HED were characterized with a decreased prevalence of multiple driver gene mutations and an immune-inflamed phenotype. Conclusions Our results unveil how HLA-B evolutionary divergence influences the ICB response in patients with GI cancers, supporting its potential utility as a combinatorial biomarker together with TMB for patient stratification in the future.

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