scholarly journals Identification of an immune gene expression signature associated with favorable clinical features in Treg-enriched patient tumor samples

2018 ◽  
Author(s):  
Kevin B. Givechian ◽  
Kamil Wnuk ◽  
Chad Garner ◽  
Stephen Benz ◽  
Hermes Garban ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Adaptive Immune Response ◽  
Gene Expression Signature ◽  
Gene Signature ◽  
Clinical Feature ◽  
Immune Gene ◽  
M1 Macrophage ◽  
Patient Prognosis

AbstractImmune heterogeneity within the tumor microenvironment undoubtedly adds several layers of complexity to our understanding of drug sensitivity and patient prognosis across various cancer types. Within the tumor microenvironment, immunogenicity is a favorable clinical feature in part driven by the antitumor activity of CD8+ T cells. However, tumors often inhibit this antitumor activity by exploiting the suppressive function of Regulatory T cells (Tregs), thus suppressing the adaptive immune response. Despite the seemingly intuitive immunosuppressive biology of Tregs, prognostic studies have produced contradictory results regarding the relationship between Treg enrichment and survival. We therefore analyzed RNA-seq data of Treg-enriched tumor samples to derive a pan-cancer gene signature able to help reconcile the inconsistent results of Treg studies, by better understanding the variable clinical association of Tregs across alternative tumor contexts. We show that increased expression of a 32-gene signature in Treg-enriched tumor samples (n=135) is able to distinguish a cohort of patients associated with chemosensitivity and overall survival This cohort is also enriched for CD8+ T cell abundance, as well as the antitumor M1 macrophage subtype. With a subsequent validation in a larger TCGA pool of Treg-enriched patients (n = 626), our results reveal a gene signature able to produce unsupervised clusters of Treg-enriched patients, with one cluster of patients uniquely representative of an immunogenic tumor microenvironment. Ultimately, these results support the proposed gene signature as a putative biomarker to identify certain Treg-enriched patients with immunogenic tumors that are more likely to be associated with features of favorable clinical outcome.

Targeting the immunosuppressive tumor microenvironment: Synergistic effect of low-dose IL12 in combination with dual immune checkpoint inhibition in a preclinical model of ovarian cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 7-7
Author(s):  
Paul G. Pavicic ◽  
Patricia A. Rayman ◽  
Hussein Al-Sudani ◽  
C. Marcela Diaz-Montero ◽  
Haider Mahdi
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Synergistic Effect ◽  
Immune Checkpoint ◽  
Low Dose ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Activated T Cells

7 Background: Epithelial ovarian cancer (OC) is the most lethal gynecologic cancer with ~22,000 women diagnosed annually in the US. The impact of immune checkpoint inhibition (ICI) in the treatment of solid tumors has been significant. However, the response rates for OC are low ranging from 11-15%. It is critical to explore strategies to enhance the efficacy of ICI immunotherapy in OC. Targeting immunosuppressive factors and cells within the tumor microenvironment (TME) represents a feasible approach. The use of IL12 is attractive because induces potent antitumor activity by targeting myeloid cells and lymphocytes. However its clinical application has been hindered by its potential systemic toxicity. Here we explore the use of low dose intraperitoneal IL12 to enhance the antitumor activity of dual ICI in OC. Methods: Mice bearing ID8-VEGF tumors implanted intraperitoneally received either anti-PD1 alone or dual ICI treatment of anti-PD1 plus anti-CTLA4 with or without low dose IL12. Ascites accumulation was used as surrogate for tumor progression and determined by assessing weight increase. Blood and ascites were analyzed by flow cytometry for frequency of PMN-MDSC, M-MDSC, and activated T cells. Results: Low dose IL12 alone induced a significant delay in ascites accumulation when compared to untreated controls or mice treated with PD1 monotherapy or dual ICI. Addition of IL12 to dual ICI resulted in significant tumor regression and extended survival benefit compared to dual ICI alone. A synergistic effect of IL12 was not observed when combined with PD1 monotherapy. Antitumor responses associated with a marked decrease in the frequency of M-MDSC in blood and a decrease in both PMN- and M-MDSC in ascites. Decrease in MDSC associated with elevated levels of activated T cells. Conclusions: Low dose IL12 can induce regression of ID8-VEGF tumors. However, durable responses were only observed when IL12 was added to dual ICI. This suggests that IL12 can induce changes in the TME, particularly on MDSC, that can potentiate the antitumor activity of dual ICI. Our findings also suggest a crucial role of CTLA4 blockade perhaps via Treg targeting.

scholarly journals A Novel Lactate Metabolism-Related Gene Signature for Predicting Clinical Outcome and Tumor Microenvironment in Hepatocellular Carcinoma

2022 ◽  
Vol 9 ◽  
Author(s):  
Yue Li ◽  
Huanye Mo ◽  
Shengli Wu ◽  
Xin Liu ◽  
Kangsheng Tu
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Tumor Microenvironment ◽  
External Validation ◽  
Gene Signature ◽  
Metabolic Reprogramming ◽  
Lactate Metabolism ◽  
Related Gene ◽  
High Group ◽  
Cox Regression Analysis

Hepatocellular carcinoma (HCC) is the main subtype of primary liver cancer with high malignancy and poor prognosis. Metabolic reprogramming is a hallmark of cancer and has great importance on the tumor microenvironment (TME). As an abundant metabolite, lactate plays a crucial role in cancer progression and the immunosuppressive TME. Nonetheless, the potential roles of lactate in HCC remain unclear. In this study, we downloaded transcriptomic data of HCC patients with corresponding clinical information from the TCGA and ICGC portals. The TCGA-HCC dataset used as the training cohort, while the ICGC-LIRI-JP dataset was served as an external validation cohort. Cox regression analysis and the LASSO regression model were combined to construct the lactate metabolism-related gene signature (LMRGS). Then, we assessed the clinical significance of LMRGS in HCC. Besides, enriched molecular functions, tumor mutation burden (TMB), infiltrating immune cells, and immune checkpoint were comprehensively analyzed in different LMRGS subgroups. In total, 66 differentially expressed lactate metabolism-related genes (LMRGs) were screened. The functions of LMRGs were mainly enriched in mitochondrial activity and metabolic processes. The LMRGS comprised of six key LMRGs (FKTN, PDSS1, PET117, PUS1, RARS1, and RNASEH1) had significant clinical value for independently predicting the prognosis of HCC patients. The overall survival and median survival of patients in the LMRGS-high group were significantly shorter than in the LMRGS-low group. In addition, there were differences in TMB between the two LMRGS subgroups. The probability of genetic mutations was higher in the LMRGS-high group. Most importantly, the LMRGS reflected the TME characteristics. In the LMRGS-high group, the immune microenvironment presented a suppressed state, accompanied by more inhibitory immune cell infiltration, including follicular helper T cells and regulatory T cells. Additionally, the expression of inhibitory checkpoint molecules was much higher in the LMRGS-high group. Our study suggested that the LMRGS was a robust biomarker to predict the clinical outcomes and evaluate the TME of patients with HCC.

scholarly journals Antiangiogenic antibody BD0801 combined with immune checkpoint inhibitors achieves synergistic antitumor activity and affects the tumor microenvironment

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Liting Xue ◽  
Xingyuan Gao ◽  
Haoyu Zhang ◽  
Jianxing Tang ◽  
Qian Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Clinical Development ◽  
Cell Mediated Immunity ◽  
Tumor Models ◽  
Anti Vegf

Abstract Background Signaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on combining anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage. Methods In this study, the anti-cancer activities of BD0801 and its potential synergistic anti-tumor effects when combined with different immunotherapies were assessed by using in vitro assays and in vivo tumor models. Ex vivo studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification. Results BD0801 showed more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). BD0801 exhibited dose-dependent tumor growth inhibitory activities in xenograft and murine syngeneic tumor models. Notably, combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies showed synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Furthermore, the mechanistic studies suggested that the MOA of the antitumor synergy involves improved tumor vasculature normalization and enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double-positive CD8+PD-1+ T cells. Conclusions These data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.

Phase I study of AMG 160, a half-life extended bispecific T-cell engager (HLE BiTE immune therapy) targeting prostate-specific membrane antigen, in patients with metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5590-TPS5590 ◽  
Author(s):  
Ben Tran ◽  
Lisa Horvath ◽  
Matthew Rettig ◽  
Karim Fizazi ◽  
Martijn P. Lolkema ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Phase I Study ◽  
Immune Therapy ◽  
Prostate Specific Membrane Antigen ◽  
Pet Ct ◽  
Specific Membrane

TPS5590 Background: Prostate-specific membrane antigen (PSMA) is a clinically validated therapeutic target for the imaging and treatment of mCRPC. AMG 160 is an HLE BiTE immune therapy designed to redirect T cells to cancer cells by binding to PSMA on cancer cells and CD3 on T cells. BiTE immune therapy leads to direct tumor cell killing, T-cell activation and expansion, and the creation of a pro-inflammatory tumor microenvironment. Combining AMG 160 with a PD-1 inhibitor may enhance antitumor activity by enabling sustained T-cell-dependent killing of tumor cells in the inflamed tumor microenvironment. Methods: NCT03792841 is a phase I study of AMG 160 as monotherapy (part 1) and in combination with pembrolizumab (part 2) in men with histologically/cytologically confirmed mCRPC who are refractory to a novel hormonal therapy (abiraterone, enzalutamide, and/or apalutamide) and have failed 1–2 taxane regimens (or are medically unsuitable or have refused taxanes), who have ongoing castration with total serum testosterone ≤ 50 ng/dL, and have evidence of progressive disease. Patients who received prior PSMA radionuclide therapy may be eligible. Patients with CNS metastases, leptomeningeal disease, spinal cord compression, or active autoimmune disease will be excluded. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of AMG 160 given as monotherapy or in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and preliminary antitumor activity. Exploratory objectives include evaluation of potential pharmacodynamic and patient selection biomarkers, immunogenicity, and patient-reported pain and functional outcomes. The part 1 dose exploration will determine the MTD/RP2D of AMG 160. The part 1 dose expansion will confirm the safety and tolerability of the MTD/RP2D. The part 2 dose exploration will estimate the MTD/RP2D of AMG 160 in combination with pembrolizumab. Evaluation of preliminary antitumor activity will be based on RECIST 1.1 with Prostate Cancer Working Group 3 modifications, PSA response, CTC response, progression-free survival (radiographic and PSA), and overall survival. PSMA PET/CT and FDG PET/CT imaging will be used for evaluation of exploratory objectives. The study opened in February 2019 and is currently recruiting patients into both part 1 and part 2. Clinical trial information: NCT03792841 .

scholarly journals Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Zoe C. Schmiechen ◽  
Ingunn M. Stromnes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Function ◽  
Adaptive Immune Response ◽  
Ductal Adenocarcinoma ◽  
Adaptive Immune ◽  
Cell Clearance

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with an overall 5-year survival rate of 10%. Disease lethality is due to late diagnosis, early metastasis and resistance to therapy, including immunotherapy. PDA creates a robust fibroinflammatory tumor microenvironment that contributes to immunotherapy resistance. While previously considered an immune privileged site, evidence demonstrates that in some cases tumor antigen-specific T cells infiltrate and preferentially accumulate in PDA and are central to tumor cell clearance and long-term remission. Nonetheless, PDA can rapidly evade an adaptive immune response using a myriad of mechanisms. Mounting evidence indicates PDA interferes with T cell differentiation into potent cytolytic effector T cells via deficiencies in naive T cell priming, inducing T cell suppression or promoting T cell exhaustion. Mechanistic research indicates that immunotherapy combinations that change the suppressive tumor microenvironment while engaging antigen-specific T cells is required for treatment of advanced disease. This review focuses on recent advances in understanding mechanisms limiting T cell function and current strategies to overcome immunotherapy resistance in PDA.

Characterization of anti-CD19 chimeric antigen receptor (CAR) T cell-mediated tumor microenvironment immune gene profile in a multicenter trial (ZUMA-1) with axicabtagene ciloleucel (axi-cel, KTE-C19).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3025-3025 ◽  
Author(s):  
Jerome Galon ◽  
John Rossi ◽  
Sarah Turcan ◽  
Corinne Danan ◽  
Frederick Lundry Locke ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Objective Response ◽  
Gene Signature ◽  
Fold Change ◽  
Immune Gene ◽  
Car T Cell ◽  
Car T

3025 Background: Axi-cel is an autologous anti-CD19 CAR T cell therapy. ZUMA-1 is a multicenter, registrational trial of axi-cel in patients (pts) with refractory/aggressive B-cell non-Hodgkin lymphoma (NHL). In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with 76% objective response rate and 47% complete response (Blood 2016;128:LBA-6). We describe, for the first time, a tumor microenvironment immune gene signature associated with CAR T cell treatment (tx) of NHL pts. Methods: Paired biopsies, pre- and within 3 weeks post-axi-cel tx, were analyzed by digital gene expression followed by a pre-specified bioinformatics algorithm applied to IGES15 and IGES21 genes involved in immune-mediated tumor regression (Immunosign; Galon Immunity 2013). Immunosign profiles expression of a pre-defined set of effector T cell, Th1, chemokine, and cytokine genes. Expression analysis and hierarchical clustering were used to define an axi-cel-related tumor immune gene signature. Wilcoxon signed rank test with multiple test correction by FDR (Benjamini-Yekutieli) was used. Results: Gene expression profile comparisons of pre- and post-axi-cel tx biopsies from 14 pts showed profound changes in gene expression within the tumor environment after infusion. The most upregulated genes post-axi-cel tx were CCL5 (RANTES), CTLA4, and GZMA (log2 fold change > 2, P< 0.05, FDR < 0.050). Immune checkpoints PD-L1 and LAG3 were also upregulated post-axi-cel (log2 fold change > 1.6, P< 0.05, FDR < 0.055). Other genes associated with T cell proliferation, homing, and effector function were also upregulated: IL-15, GZMK, CXC3CL1 (Fractalkine), CD8A, and STAT4 (log2 fold change > 1.6; P< 0.05, FDR < 0.074). Additional baseline tumor characteristics and associative analysis will be presented. Conclusions: We define a mechanistic tumor immune gene signature in NHL pts associated with axi-cel tx. This signature comprises upregulation of T cell activation, effector, chemokine, and immune checkpoint genes. These data will potentially lead to rational optimization of T cell interventions in cancer Clinical trial information: NCT02348216.

First-in-human phase Ib study of ATRC-101, an engineered version of a patient-derived antibody targeting a tumor-restricted ribonucleoprotein complex.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3168-TPS3168
Author(s):  
Jonathan Eliot Benjamin ◽  
Nicholas Higgins ◽  
Carl Millward ◽  
Jeff Defalco ◽  
Amy Manning-Bog ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Single Agent ◽  
Human Tumor ◽  
Lymphoid Cells ◽  
Mouse Tumor ◽  
Acral Melanoma ◽  
M1 Macrophage ◽  
Wide Range

TPS3168 Background: ATRC-101 is a fully human, engineered IgG1 version of an antibody discovered through a a target-agnostic screen to identify patient-derived antibodies that bind selectively to public tumor antigens. The parental antibody was identified from B cells in the active immune response of a patient receiving checkpoint therapy for Stage IV non-small cell lung cancer (NSCLC). A fluorescently conjugated version of ATRC-101 binds selectively to human tumor specimens including a majority of NSCLC, acral melanoma, breast, colorectal, and ovarian cancer samples. No reactivity of toxicological significance is found across a wide range of normal human tissues. ATRC-101 displays dose-dependent, single-agent activity in syngeneic mouse tumor models, including the EMT6 breast cancer model, which displays a T cell-excluded microenvironment often observed in human tumors, and in which checkpoint inhibitors targeting the PD-1 axis exhibit limited activity. Dosing with ATRC-101 in the EMT6 model causes marked changes in the tumor microenvironment, including a shift from the M2 to the M1 macrophage phenotype and infiltration of T cells. ATRC-101 does not appear to act via NK cell-driven ADCC; instead, activity in vivo is dependent both on Fc region interactions with Fc receptors, likely on myeloid rather than lymphoid cells, and on the presence of CD8+ T cells. ATRC-101 binds to a target that is a ribonucleoprotein (RNP) complex containing polyadenylate-binding protein 1 (PABP-1) bound to poly(A)RNA. Whereas both PABP-1 and poly(A)RNA are ubiquitously expressed at high levels in normal tissues and have been localized intracellularly, the ATRC-101 target is detected extracellularly on tumor cells grown in vivo. The basis for the tumor-selectivity of ATRC-101 as well as the extracellular localization of the target is under investigation. Ascending doses of ATRC-101 were well tolerated in multiple non-clinical safety studies. Methods: ATRC-101-A01 is an open-label, 3+3, Phase 1b safety study in patients with acral melanoma, NSCLC, breast, ovarian, and colorectal cancers. Participants are accruing in the first dose cohort. ATRC-101 is administered every 21 days up to 24 months or until disease progression. The primary objective of the trial is to determine the safety and tolerability of ATRC-101. Secondary objectives are to characterize the pharmacokinetic profiles of ATRC-101 and to assess antitumor activity as determined by RECIST 1.1 and lymphocytic infiltration in the tumor microenvironment. Clinical trial information: NCT04244552 .

438 Synergy between SEA-CD40 and chemotherapeutics drives curative antitumor activity in preclinical models

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A464-A464
Author(s):  
Weiping Zeng ◽  
Haley Neff-LaFord ◽  
Sahar Ansari ◽  
Celine Jacquemont ◽  
Michael Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Cell Activation ◽  
Tumor Antigens ◽  
Immune Cell ◽  
Chemotherapeutic Agents ◽  
Clinical Development ◽  
Immune Cell Activation

BackgroundCD40 is a co-stimulatory receptor of the TNF receptor superfamily expressed on antigen presenting cells (APCs). Antibodies targeting CD40 may have antitumor therapeutic benefit by driving innate immune cell activation that supports generation of antigen-specific T cell responses. Multiple CD40-directed antibodies are in clinical development in both solid and hematologic indications and differ according to immunoglobulin isotype, affinity to CD40, and differential FcγR-binding. SEA-CD40 is an agonistic nonfucosylated, humanized IgG1 monoclonal antibody directed against CD40. SEA-CD40 is distinct from other CD40 targeted agents in clinical development as it binds with increased affinity to FcγRIIIa resulting in enhanced effector function and CD40 agonism. This unique composition of SEA-CD40 could amplify immune stimulation and antitumor activity relative to other CD40-directed therapeutics.MethodsEffective immunity requires the presence of diverse antigens to drive generation of distinct antigen-specific memory T cells. SEA-CD40 in many ways works like a vaccine as it can increase active acquired immunity against endogenous tumor antigens. A potential limiting factor for maximal SEA-CD40 antitumor activity across multiple tumor types may be the limited level and diversity of tumor-associated antigens within the tumor microenvironment (TME). Chemotherapeutic agents drive tumor cell death resulting in the release and increase of tumor antigens locally within the TME. Combining chemotherapeutic agents with SEA-CD40 could facilitate robust antigen release and amplified presentation of those antigens to CD8+ T cells. Antitumor activity and immune cell changes of SEA-CD40 in combination with chemotherapeutic agents was evaluated in vitro and in vivo using human CD40 transgenic mice.ResultsIn preclinical mouse models, SEA-CD40 combined with chemotherapeutic agents to drive robust anti-tumor activity. The nature of the chemotherapeutic agent influenced immune cell activation within the tumor microenvironment (TME) and extent of combinability with SEA-CD40. Preclinical assessment indicates that chemotherapeutics which induce immunogenic cell death (ICD) combine with SEA-CD40 to increase curative activity compared to non-ICD-inducing chemotherapeutics. The preferred partnership of SEA-CD40 with ICD-inducing agents, such as a monomethyl auristatin E (MMAE) antibody-drug conjugate, increased curative antitumor activity in mouse models. The combination of SEA-CD40 and chemotherapeutic agents with a T cell targeted anti-PD1 antibody could deepen and extend these anti-tumor responses.ConclusionsThese data support continued clinical evaluation of SEA-CD40 in combination with chemotherapeutic agents and potentially in the future MMAE based ADCs. A phase 1 clinical trial is actively enrolling (NCT02376699) and includes a cohort in pancreatic cancer assessing the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab.Ethics ApprovalStudies with human samples were performed according to institutional ethics standards. Animals studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-029.

scholarly journals Identification of a Tumor Microenvironment-Related Gene Signature Indicative of Disease Prognosis and Treatment Response in Colon Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-31
Author(s):  
Wenzheng Chen ◽  
Jianfeng Huang ◽  
Jianbo Xiong ◽  
Pengcheng Fu ◽  
Changyu Chen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Tumor Microenvironment ◽  
Treatment Response ◽  
Risk Group ◽  
Gene Expression Signature ◽  
Gene Signature ◽  
High Risk Group ◽  
Related Gene ◽  
Cox Regression Analysis

Background. The tumor microenvironment (TME) is associated with disease outcomes and treatment response in colon cancer. Here, we constructed a TME-related gene signature that is prognosis of disease survival and may predict response to immunotherapy in colon cancer. Methods. We calculated immune and stromal scores for 385 colon cancer samples from The Cancer Genome Atlas (TCGA) database using the ESTIMATE algorithm. We identified nine TME-related prognostic genes using Cox regression analysis. We evaluated associations between protein expression, extent of immune cell infiltrate, and patient survival. We calculated risk scores and built a clinical predictive model for the TME-related gene signature. Receiver operating characteristic (ROC) curves were generated to assess the predictive power of the signature. We estimated the half-maximal inhibitory concentration (IC50) of chemotherapeutic drugs in patients using the pRRophetic algorithm. The expression of immune checkpoint genes was evaluated. Results. High immune and stromal scores are significantly associated with poor overall survival ( p < 0.05 ). We identified 773 differential TME-related prognostic genes associated with survival; these genes were enriched in immune-related pathways. Nine key prognostic genes were identified and were used to construct a TME-related prognostic signature: CADM3, LEP, CD1B, PDE1B, CCL22, ABI3BP, IGLON5, SELE, and TGFB1. This signature identified a high-risk group with worse survival outcomes, based on Kaplan-Meier analysis. A nomogram composed of clinicopathological factors and risk score exhibited good accuracy. Drug sensitivity analysis identified no difference in sensitivity between the high-risk and low-risk groups. High-risk patients had higher expression of PD-1, PDL-1, and CTLA-4 and lower expression of LAG-3 and VSIR. Infiltration of dendritic cells was higher in the high-risk group. Conclusions. We identified a novel prognostic TME-related gene expression signature in colon cancer. Stratification of patients based on this gene signature could be used to improve outcomes and guide better therapy for colon cancer patients.

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