High-throughput single-сell sequencing in cancer research

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: May 3, 2022

Abstract With advances in sequencing and instrument technology, bioinformatics analysis is being applied to batches of massive cells at single-cell resolution. High-throughput can be utilized for multi-omics characterization tumor cells, stromal or infiltrated immune evaluate progression, responses environmental perturbations, heterogeneous composition the microenvironment, complex intercellular interactions between these factors. Particularly, T cell receptors, alone combination with RNA sequencing, useful fields immunology immunotherapy. Clinical insights obtained from are critically important exploring biomarkers disease progression antitumor treatment, as well guiding precise clinical decision-making patients malignant tumors. In this review, we summarize applications evolution, immunology, Additionally, analyze response heterogeneity resistance checkpoint The limitations cancer research also discussed.

Language: Английский

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Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Oct. 8, 2022

Non-inflamed tumors, including immune-excluded and immune-desert are commonly resistant to anti-PD-1/PD-L1 (α-PD-1/PD-L1) therapy. Our previous study reported the potent antitumor activity of anti-TGF-β/PD-L1 bispecific antibody YM101 in tumors. However, had limited models. MSA-2 is a novel oral stimulator interferon genes (STING) agonist, which activates innate immune system may synergize with overcoming immunotherapy resistance.The dose-dependent effect on STING signaling was determined by interferon-β level. The maturation function dendritic cell (DC) were measured flow cytometry, RNA-seq, one-way mixed lymphocyte reaction (MLR), OVA peptide pulse, cytokine/chemokine detection. synergistic between assessed MLR. macrophage activation cytometry vivo combined explored syngeneic murine tumor After treatments, alterations microenvironment (TME) detected immunohistochemistry staining, immunofluorescence single-cell RNA-seq (scRNA-seq).MSA-2 could promote antigen presentation capability DC. In MLR assay, synergized enhancing naive T activation. Moreover, stimulated classical macrophage, without significant influence alternative Further explorations showed that increased multiple proinflammatory cytokines chemokines TME. remarkedly retarded growth models, superior monotherapies. Flow bulk scRNA-seq assays indicated combination therapy simultaneously boosted adaptive immunity, promoted presentation, improved migration chemotaxis, upregulated numbers activities tumor-infiltrating lymphocytes.Our results demonstrate synergizes boosting immunity. This cocktail effectively overcomes resistance

Language: Английский

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Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy

Cancer Cell, Journal Year: 2022, Volume and Issue: 40(6), P. 674 - 693.e7

Published: May 19, 2022

Language: Английский

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Titin mutation associated with responsiveness to checkpoint blockades in solid tumors

JCI Insight, Journal Year: 2019, Volume and Issue: 4(10)

Published: May 15, 2019

Immune checkpoint blockade (ICB) immunotherapy induces potent antitumor immunity across multiple solid tumors, although few patients respond well to this therapy. An emerging biomarker for predicting responsiveness ICB is tumor mutational burden (TMB). Although several surrogate biomarkers, including deficient mismatch repair, TP53/KRAS mutations, and comutations in DNA damage response pathways, have been shown be effective the immunotherapy, each positive only a small cohort of candidates, many potential responders are inevitably missed. Here, we found that titin (TTN), which frequently detected associated with increased TMB correlated objective ICB. In 7 public clinical cohorts, all mutated TTN showed longer progression-free survival or overall than those wild-type status. Furthermore, an improved rate higher were identified cohorts accessible information. Identification mutation as predictor outcomes ICBs provides clinically feasible assessment estimating therapy outcomes.

Language: Английский

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Spatially fractionated radiation therapy: History, present and the future

Clinical and Translational Radiation Oncology, Journal Year: 2019, Volume and Issue: 20, P. 30 - 38

Published: Oct. 23, 2019

Spatially Fractionated Radiation therapy (SFRT) has a history of over 100 years. The principle SFRT is distinctive from the standard radiation approaches, as it treats total tumor with non-uniform dose, effectively treating while staying within normal tissue tolerance surrounding structures. Historically, frequently used to treat bulky malignant tumors high dose in stereotactic radiosurgery (SRS)/stereotactic body radiotherapy (SBRT) range (10–20 Gy per fraction) using megavoltage x-ray beams.

Language: Английский

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Non-Genetic Intra-Tumor Heterogeneity Is a Major Predictor of Phenotypic Heterogeneity and Ongoing Evolutionary Dynamics in Lung Tumors

Cell Reports, Journal Year: 2019, Volume and Issue: 29(8), P. 2164 - 2174.e5

Published: Nov. 1, 2019

Impacts of genetic and non-genetic intra-tumor heterogeneity (ITH) on tumor phenotypes evolvability remain debated. We analyze ITH in lung squamous cell carcinoma at the levels genome, transcriptome, tumor-immune interactions histopathological characteristics by multi-region bulk single-cell sequencing. Genomic alone is a weak indicator immune transcriptomic that impact multiple cancer-related pathways, including those related to proliferation inflammation, which turn contribute regional differences histopathology subtype classification. Tumor subclones have substantial score, suggestive non-neutral clonal dynamics. Proliferation other pathways also show differences, sometimes even within same subclones. Neo-epitope burden negatively correlates with infiltration, indicating immune-mediated purifying selection somatic mutations. Taken together, our observations suggest major determinant impacts evolutionary dynamics cancer.

Language: Английский

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Beyond Tumor Mutation Burden: Tumor Neoantigen Burden as a Biomarker for Immunotherapy and Other Types of Therapy

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 11

Published: April 29, 2021

Immunotherapy has significantly improved the clinical outcome of patients with cancer. However, immune response rate varies greatly, possibly due to lack effective biomarkers that can be used distinguish responders from non-responders. Recently, studies have associated high tumor neoantigen burden (TNB) outcomes in treated immunotherapy. Therefore, TNB emerged as a biomarker for immunotherapy and other types therapy. In present review, potential application was evaluated. The methods prediction were summarized mechanisms involved investigated. impact increased number infiltrating cells on efficacy also addressed. Finally, future challenges discussed.

Language: Английский

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Baseline Plasma Tumor Mutation Burden Predicts Response to Pembrolizumab-based Therapy in Patients with Metastatic Non–Small Cell Lung Cancer

Clinical Cancer Research, Journal Year: 2020, Volume and Issue: 26(10), P. 2354 - 2361

Published: Feb. 26, 2020

Abstract Purpose: The role of plasma-based tumor mutation burden (pTMB) in predicting response to pembrolizumab-based first-line standard-of-care therapy for metastatic non–small cell lung cancer (mNSCLC) has not been explored. Experimental Design: A 500-gene next-generation sequencing panel was used assess pTMB. Sixty-six patients with newly diagnosed mNSCLC starting therapy, either alone or combination chemotherapy, were enrolled (Clinicaltrial.gov identifier: NCT03047616). Response assessed using RECIST 1.1. Associations made patient characteristics, 6-month durable clinical benefit (DCB), progression-free survival (PFS), and overall (OS). Results: Of 66 patients, 52 (78.8%) pTMB-evaluable. Median pTMB 16.8 mutations per megabase (mut/Mb; range, 1.9–52.5) significantly higher achieving DCB compared no (21.3 mut/Mb vs. 12.4 mut/Mb, P = 0.003). For ≥ 16 median PFS 14.1 versus 4.7 months < [HR, 0.30 (0.16–0.60); 0.001]. OS reached 8.8 0.48 (0.22–1.03); 0.061]. Mutations ERBB2 exon 20, STK11, KEAP1, PTEN more common DCB. absence negative predictor associated 0.24 (0.11–0.49); 0.001] 0.31 (0.13–0.74); 0.009]. Conclusions: is improved after mNSCLC. STK11/KEAP1/PTEN may help identify pTMB-high unlikely respond. These results should be validated larger prospective studies.

Language: Английский

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Highlights in Resistance Mechanism Pathways for Combination Therapy

Cells, Journal Year: 2019, Volume and Issue: 8(9), P. 1013 - 1013

Published: Aug. 30, 2019

Combination chemotherapy has been a mainstay in cancer treatment for the last 60 years. Although mechanisms of action and signaling pathways affected by most treatments with single antineoplastic agents might be relatively well understood, combinations remain poorly understood. This review presents common alterations response to cytotoxic targeted anticancer drug treatments, discussion how knowledge support orient development innovative strategies combination therapy. The ultimate goal is highlight possible based on associated resistance against drugs maximize selective induction cell death. We consider this an extensive compilation updated known information promote new therapies discussed tested.

Language: Английский

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Identification of an Immune Signature Predicting Prognosis Risk and Lymphocyte Infiltration in Colon Cancer

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Sept. 3, 2020

Increasing studies have pointed out the effects of tumor immune microenvironment (TIM) on colon cancer (CC) tumorigenesis, prognosis and metastasis. However, there has no reliable molecular marker that can effectively estimate infiltration predict CC relapse risk. Here, we leveraged gene expression profile clinical characteristics from 1430 samples, including four GEO databases TCGA database, to construct an risk signature could be used as a predictor survival outcome activity. A model consisting 10 immune-related genes were screened in LASSO-cox then aggregated generate based regression coefficients. The demonstrated robust prognostic ability discovery validation datasets, this association remained significant multivariate analysis after controlling for age, gender, stage or MSI status. Leucocyte subpopulation indicated low-risk was enriched with cytotoxic cells (activated CD4/CD8+ T cell NK cell) depleted MDSC regulatory cell. Further patients harbored higher mutation load lower mutational frequencies significantly mutated APC FBXW7. Together, our constructed represent TIM CC, which promotes individualized treatment provides promising novel immunotherapy.

Language: Английский

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