Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer

Nature Medicine, Journal Year: 2020, Volume and Issue: 26(5), P. 732 - 740

Published: April 27, 2020

Language: Английский

---

Resistance Mechanisms to Anti-PD Cancer Immunotherapy

Annual Review of Immunology, Journal Year: 2022, Volume and Issue: 40(1), P. 45 - 74

Published: April 26, 2022

The transformative success of antibodies targeting the PD-1 (programmed death 1)/B7-H1 (B7 homolog 1) pathway (anti-PD therapy) has revolutionized cancer treatment. However, only a fraction patients with solid tumors and some hematopoietic malignancies respond to anti-PD therapy, reason for failure in other is less known. By dissecting mechanisms underlying this resistance, current studies reveal that tumor microenvironment major location resistance occur. Furthermore, appear be highly heterogeneous. Here, we discuss recent human data identifying therapy. We review evidence immune-based such as loss neoantigens, defects antigen presentation interferon signaling, immune inhibitory molecules, exclusion T cells. also clinical emerging alterations metabolism, microbiota, epigenetics. Finally, strategies overcome therapy emphasize need develop additional immunotherapies based on concept normalization immunotherapy.

Language: Английский

---

Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(24)

Published: June 7, 2021

Significance Renal cell carcinomas (RCCs) are heterogeneous malignancies thought to arise from kidney tubular epithelial cells, and clear RCC is the most common entity. This study demonstrates that atlases generated benign two RCCs using single-cell RNA sequencing can predict putative cells of origin for more than 10 subtypes. A focused analysis distinct cell-type compartments reveals potential role tumor epithelia in promoting immune infiltration other molecular attributes microenvironment. Finally, an observed association between lack immunotherapy response endothelial fraction has important clinical implications. The current study, therefore, significantly contributes toward understanding disease ontogenies dynamics

Language: Английский

---

Molecular Features of Cancer-associated Fibroblast Subtypes and their Implication on Cancer Pathogenesis, Prognosis, and Immunotherapy Resistance

Clinical Cancer Research, Journal Year: 2021, Volume and Issue: 27(9), P. 2636 - 2647

Published: Feb. 23, 2021

Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment, but a systematic investigation their molecular characteristics and clinical relevance lacking. Here, we sought to compare CAFs across multiple cancer types identify critical pathways activated in CAF subtypes, which may contribute outcome, disease progression, immunotherapy resistance.We performed integrated analysis from melanoma, head neck squamous cell carcinoma, lung cancer, identified that distinctly active each subtype. Gene signatures for individual subtypes were used study association subtype abundance with outcome six (pan-CAF) shared uncovered genetic distinguishing them. Interestingly, these express distinct immunosuppressive factors, such as CXCL12 CXLC14, stem cell-promoting factor IL6. In addition, novel transcriptional drivers (MEF2C, TWIST1, NR1H3, RELB, FOXM1) key heterogeneity. Furthermore, showed associated different outcomes could activate or suppress progression involved resistance anti-PD1 anti-PD-L1 immunotherapy.Our identifies several types, implicates benefit targeted therapies, specific resistance.

Language: Английский

---

Geospatial immune variability illuminates differential evolution of lung adenocarcinoma

Nature Medicine, Journal Year: 2020, Volume and Issue: 26(7), P. 1054 - 1062

Published: May 27, 2020

Language: Английский

---

TCR Repertoire Diversity of Peripheral PD-1+CD8+ T Cells Predicts Clinical Outcomes after Immunotherapy in Patients with Non–Small Cell Lung Cancer

Cancer Immunology Research, Journal Year: 2019, Volume and Issue: 8(1), P. 146 - 154

Published: Nov. 12, 2019

Abstract T-cell receptor (TCR)–based biomarkers might predict patient response to immune checkpoint blockade (ICB) but need further exploration and validation for that use. We sequenced complementarity-determining region 3 of TCRβ chains isolated from PD-1+ CD8+ T cells investigate its value predicting the anti–programmed cell death 1 (PD-1)/PD-ligand (PD-L1) therapy in patients with non–small lung cancer (NSCLC). Two independent cohorts (cohort A, n = 25; cohort B, 15) were used as discovery sets, respectively. Pre- post-ICB peripheral blood samples collected. In high TCR diversity before ICB treatment showed better progression-free survival (PFS) compared low [6.4 months vs. 2.5 months, HR, 0.39; 95% confidence interval (CI), 0.17–0.94; P 0.021]. The results validated B. Pre-ICB achieved an optimal Youden's index 0.81 (sensitivity 0.87 specificity 0.94) differentiating merged dataset A plus B). Patients increased clonality after had longer PFS (7.3 2.6 0.26; CI, 0.08–0.86; 0.002) than those decreased clonality. Thus, may serve noninvasive predictors outcomes NSCLC.

Language: Английский

---

Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non–Small Cell Lung Cancer

JAMA Network Open, Journal Year: 2019, Volume and Issue: 2(7), P. e196879 - e196879

Published: July 10, 2019

Importance

The beneficial role of immunotherapy and the clinical relevance current biomarkers in non–small cell lung cancer (NSCLC) remain inconclusive; thus, appropriate strategies reliable predictors need further definition.

Objectives

To evaluate association outcomes with immune checkpoint inhibitors, tumor vaccines, cellular patients advanced NSCLC to explore strategies, candidates, predictors.

Data Sources

PubMed, EMBASE, Cochrane Central Register Controlled Trials databases were searched from inception June 2018, using relevant search keywords Medical Subject Headings (MeSH) terms, includingtumor vaccine,cellular immunotherapy,immune inhibitor,cytotoxic T-lymphocyte-associated protein 4,programmed death-ligand 1,programmed death receptor 1, andnon-small carcinoma. Systematic reviews, meta-analyses, references, conference proceedings manually searched.

Study Selection

English-language randomized trials available data that measured overall survival (OS), progression-free (PFS), or objective response rate comparing conventional therapy for metastatic included. Thirty-one included, multicohort included next-generation sequencing NCSLC. Extraction Synthesis Hazard ratios 95% CIs pooled estimate increases OS PFS. Dichotomous data, such as object analyzed risk ratio. Mantel-Haenszel random-effects model was used.I²was used assess heterogeneity between trials; anI²value exceeding 50% indicated existence substantial heterogeneity. Analyses took place February 1, August 31, 2018.

Main Outcomes Measures

Primary

Results

In total, 14 395 (9500 [66.0%] men) meta-analysis, 1833 (mean [SD], 65.2 [9.9] years; 1063 [58.0%] individual patient–level study. Compared therapy, associated significantly longer (hazard ratio, 0.76; CI, 0.71-0.82;P < .001) PFS 0.70-0.83;P .001). best blockade strategy first-line pembrolizumab platinum-based chemotherapy. combined predictive utility programmed ligand 1 (PD-L1) expression mutation burden (TMB) prognosis (whole-exome sequencing: 1-year area under receiver operating characteristic curve [AUC], 0.829; 3-year AUC, 0.839; targeted 0.826; 0.948). Moreover, addition CD8⁺T-cell tumor-infiltrating lymphocytes improved predictions (3-year 0.659; 5-year 0.665).RYR1orMGAMmutations concomitantly increased durable benefits (RYR1: benefit [DCB], 12 51 [24%]; no [NDB], 2 55 [4%];P .001;MGAM: DCB, NDB, 0 patients;P .001), a higher TMB (RYRI: high TMB, 53 [23%]; low [38%];P 9 [17%]; PD-L1 expression, 8 30 [27%]; 6 85 [7.1%];P [20%]; 5 [6%];P

Conclusions Relevance

Immunotherapies showed promising NSCLC. Pembrolizumab chemotherapy found be most inhibitor regimen NSCLC, use biomarker patients’ precision immunotherapy. combination lymphocytes, prognosis. value needs prospectively validated large-scale studies.

Language: Английский

---

m⁶A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer

Theranostics, Journal Year: 2020, Volume and Issue: 11(5), P. 2201 - 2217

Published: Dec. 16, 2020

Recent studies have highlighted the biological significance of RNA N6-methyladenosine (m6A) modification in tumorigenicity and progression. However, it remains unclear whether m6A modifications also potential roles immune regulation tumor microenvironment (TME) formation. Methods: In this study, we curated 23 regulators performed consensus molecular subtyping with NMF algorithm to determine patterns m6A-related gene signature colon cancer (CC). The ssGSEA CIBERSORT algorithms were employed quantify relative infiltration levels various cell subsets. An PCA based m6Sig scoring scheme was used evaluate individual tumors an response. Results: Three distinct identified among 1307 CC samples, which associated different clinical outcomes pathways. TME characterization revealed that highly consistent three known profiles: immune-inflamed, immune-excluded, immune-desert, respectively. Based on score, extracted from genes, patients can be divided into high low score subgroups. Patients lower characterized by prolonged survival time enhanced infiltration. Further analysis indicated correlated greater mutation loads, PD-L1 expression, higher rates SMGs (e.g., PIK3CA SMAD4). addition, scores showed a better responses durable benefits independent immunotherapy cohorts. Conclusions: This study highlights is significantly diversity complexity. Quantitatively evaluating will strengthen our understanding characteristics promote more effective strategies.

Language: Английский

---

Colorectal Cancer‐Derived Small Extracellular Vesicles Promote Tumor Immune Evasion by Upregulating PD‐L1 Expression in Tumor‐Associated Macrophages

Advanced Science, Journal Year: 2022, Volume and Issue: 9(9)

Published: Jan. 17, 2022

Tumor-associated macrophages (TAMs) are one of the most abundant cell types in colorectal cancer (CRC) tumor microenvironment (TME). Recent studies observed complicated "cross-talks" between cells and TME. However, underlying mechanisms still poorly elucidated. Here, PD-L1 levels very low CRC but highly TAMs, a specific PD-L1+ CD206+ macrophage subpopulation identified, which is induced by associated with poor prognosis. Mechanistic investigations reveal that can secrete small extracellular vesicles (sEVs) taken up induce M2 like polarization expression, resulting increased abundance decreased T activity sEV-derived miR-21-5p miR-200a identified as key signaling molecules mediating regulatory effects on macrophages. Further CRC-derived synergistically induces expression regulating PTEN/AKT SCOS1/STAT1 pathways, CD8+ growth. This study suggests inhibiting secretion sEV-miRNAs from targeting TAMs may serve novel methods for treatment well sensitization method anti-PD-L1 therapy CRC.

Language: Английский

---

Heterogeneity of the tumor immune microenvironment and its clinical relevance

Experimental Hematology and Oncology, Journal Year: 2022, Volume and Issue: 11(1)

Published: April 23, 2022

During the course of tumorigenesis and subsequent metastasis, malignant cells gradually diversify become more heterogeneous. Consequently, tumor mass might be infiltrated by diverse immune-related components, including cytokine/chemokine environment, cytotoxic activity, or immunosuppressive elements. This immunological heterogeneity is universally presented spatially varies temporally along with evolution therapeutic intervention across almost all solid tumors. The anti-tumor immunity shows a profound association progression disease responsiveness to treatment, particularly in realm immunotherapy. Therefore, an accurate understanding essential for development effective therapies. Facilitated multi-regional -omics sequencing, single cell longitudinal liquid biopsy approaches, recent studies have demonstrated potential investigate complexity tumors its clinical relevance Here, we aimed review mechanism underlying immune microenvironment. We also explored how assessments facilitate personalized

Language: Английский

---