Ensemble deep learning enhanced with self-attention for predicting immunotherapeutic responses to cancers

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Дек. 1, 2022

Despite the many benefits immunotherapy has brought to patients with different cancers, its clinical applications and improvements are still hindered by drug resistance. Fostering a reliable approach identifying sufferers who sensitive certain immunotherapeutic agents is of great relevance.We propose an ELISE (Ensemble Learning for Immunotherapeutic Response Evaluation) pipeline generate robust highly accurate predicting individual responses immunotherapies. employed iterative univariable logistic regression select genetic features patients, using Monte Carlo Tree Search (MCTS) tune hyperparameters. In each trial, selected multiple models integration based on add or concatenate stacking strategies, including deep neural network, automatic feature interaction learning via self-attentive networks, factorization machine, compressed linear then adopted best trial final approach. SHapley Additive exPlanations (SHAP) algorithm was applied interpret ELISE, which validated in independent test set.Regarding prediction atezolizumab within esophageal adenocarcinoma (EAC) demonstrated superior accuracy (Area Under Curve [AUC] = 100.00%). AC005786.3 (Mean [|SHAP value|] 0.0097) distinguished as most valuable contributor output, followed SNORD3D (0.0092), RN7SKP72 (0.0081), EREG (0.0069), IGHV4-80 (0.0063), MIR4526 (0.0063). Mechanistically, immunoglobulin complex, production, adaptive immune response, antigen binding others, were downregulated ELISE-neg EAC subtypes resulted unfavorable responses. More encouragingly, could be extended accurately estimate responsiveness various against other PD1/PD-L1 suppressor metastatic urothelial cancer (AUC 88.86%), MAGE-A3 melanoma 100.00%).This study presented insights into integrating ensemble self-attention mechanism human highlighting potential tool approaches individualized treatment.

Язык: Английский

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CD40L-armed oncolytic herpes simplex virus suppresses pancreatic ductal adenocarcinoma by facilitating the tumor microenvironment favorable to cytotoxic T cell response in the syngeneic mouse model

Journal for ImmunoTherapy of Cancer, Год журнала: 2022, Номер 10(1), С. e003809 - e003809

Опубликована: Янв. 1, 2022

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers worldwide. Despite promising outcome immune checkpoint inhibitors and agonist antibody therapies in different malignancies, PDAC exhibits high resistance due to its immunosuppressive tumor microenvironment (TME). Ameliorating TME thus a rational strategy for therapy. The intratumoral application oncolytic herpes simplex virus-1 (oHSV) upregulates pro-inflammatory macrophages lymphocytes TME, enhances responsiveness immunotherapy. However, antitumor activity oHSV remains be maximized. aim this study investigate effect CD40L armed on microenvironment, ultimately prolong survival mouse model.The membrane-bound form murine was engineered into by CRISPR/Cas9-based gene editing. oHSV-CD40L induced cytopathic immunogenic cell death were determined microscopy flow cytometry. expression function assessed reporter assay. administrated intratumorally competent syngeneic model, leukocytes tumor-draining lymph node analyzed multicolor Intratumoral cytokines ELISA.Intratumoral efficiently restrained growth prolonged model. In oHSV-CD40L-treated accommodated more maturated dendritic cells (DCs), which turn activated T helper 1 cytotoxic CD8+ an interferon-γ-dependent interleukin-12-dependent manner. contrast, regulatory significantly reduced treatment. Repeated dosing combinational therapy extended lifespan mice.CD40L-armed endues with increased DCs maturation DC-dependent activation cells, prolongs model mice. This may lead understanding development as synergy blockade.

Язык: Английский

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Nanoparticle-based therapeutic strategies targeting major clinical challenges in pancreatic cancer treatment

Advanced Drug Delivery Reviews, Год журнала: 2022, Номер 187, С. 114357 - 114357

Опубликована: Май 21, 2022

Язык: Английский

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A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer

Clinical Cancer Research, Год журнала: 2023, Номер 30(4), С. 655 - 662

Опубликована: Окт. 13, 2023

Abstract KRAS mutations drive oncogenic alterations in numerous cancers, particularly human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have mutations, with G12D (∼42% cases) and G12V (∼32% being the most common. The recent approval sotorasib (AMG510), a small-molecule, covalent, selective KRASG12C inhibitor, for treating patients non–small cell lung cancer represents breakthrough targeted therapy. However, there is need to develop other much-needed KRAS-mutant inhibitors PDAC Notably, Mirati Therapeutics recently developed MRTX1133, noncovalent, KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent vitro vivo antitumor efficacy against KRASG12D-mutant cells, especially PDAC, leading its initiation phase I/II clinical trial. Here, we provide summary advancements related use focusing on underlying mechanistic actions. In addition, discuss potential challenges future directions therapy including overcoming intrinsic acquired resistance, developing effective combination therapies, improving MRTX1133’s oral bioavailability target spectrum. promising results obtained from preclinical studies suggest that could revolutionize treatment bringing about paradigm shift management.

Язык: Английский

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Targeting tumor immunosuppressive microenvironment for pancreatic cancer immunotherapy: Current research and future perspective

Frontiers in Oncology, Год журнала: 2023, Номер 13

Опубликована: Март 29, 2023

Pancreatic cancer is one of the most malignant tumors with increased incidence rate. The effect surgery combined chemoradiotherapy on survival patients unsatisfactory. New treatment strategy such as immunotherapy need to be investigated. accumulation desmoplastic stroma, infiltration immunosuppressive cells including myeloid derived suppressor (MDSCs), tumor associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and regulatory T (Tregs), well cytokine TGF-β, IL-10, IL-35, CCL5 CXCL12 construct an microenvironment pancreatic cancer, which presents challenges for immunotherapy. In this review article, we explore roles mechanism lymphocytes in establishing cancer. addition, strategies based immune checkpoint inhibitors, targeting extracellular matrix (ECM), interfering stromal or cytokines TME, vaccines vesicles (EVs) are also discussed. It necessary identify approach combination other modalities produce a synergistic response rates therapy.

Язык: Английский

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