scholarly journals Temporal single-cell tracing reveals clonal revival and expansion of precursor exhausted T cells during anti-PD-1 therapy in lung cancer

Nature Cancer ◽  
2021 ◽  
Author(s):  
Baolin Liu ◽  
Xueda Hu ◽  
Kaichao Feng ◽  
Ranran Gao ◽  
Zhiqiang Xue ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Single Cell ◽  
Clinical Success ◽  
Cell Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Peripheral T Cells ◽  
Underlying Mechanisms ◽  
Tumor Biopsies

AbstractAnti-PD-1 treatment has shown unprecedented clinical success in the treatment of non-small-cell lung cancer (NSCLC), but the underlying mechanisms remain incompletely understood. Here, we performed temporal single-cell RNA and paired T-cell receptor sequencing on 47 tumor biopsies from 36 patients with NSCLC following PD-1-based therapies. We observed increased levels of precursor exhausted T (Texp) cells in responsive tumors after treatment, characterized by low expression of coinhibitory molecules and high expression of GZMK. By contrast, nonresponsive tumors failed to accumulate Texp cells. Our data suggested that Texp cells were unlikely to be derived from the reinvigoration of terminally exhausted cells; instead, they were accumulated by (1) local expansion and (2) replenishment by peripheral T cells with both new and pre-existing clonotypes, a phenomenon we named clonal revival. Our study provides insights into mechanisms underlying PD-1-based therapies, implicating clonal revival and expansion of Texp cells as steps to improve NSCLC treatment.

scholarly journals Single-cell Profiling of Immune cells After Neoadjuvant Pembrolizumab and Chemotherapy in ⅢA non-small cell lung cancer (NSCLC)

2021 ◽  
Author(s):  
Xiubao Ren ◽  
Zhenzhen Hui ◽  
Jiali Zhang ◽  
Yulin Ren ◽  
XIAOLING LI ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Clinical Outcome ◽  
Small Cell Lung Cancer ◽  
Single Cell ◽  
Immune Cells ◽  
Peripheral Blood ◽  
Small Cell ◽  
Small Cell Lung ◽  
Clinical Responses

Abstract The combination of immune checkpoint inhibitors (ICIs) with chemotherapy (chemoimmunotherapy) in the neoadjuvant setting have achieved favorable clinical benefits in non-small cell lung cancer (NSCLC), but the mechanism of clinical responses remain unclear. To identify factors associated with the clinical outcome, we provide a rich resource of 186,477 individual immune cells from matched multiple immune-relevant tissue sites and peripheral blood of four treatment-naïve and eight neoadjuvant chemoimmunotherapy treated ⅢA NSCLC patients (responders versus non-responders) by single-cell RNA-seq and TCR-seq. We showed that the synergistic increase of B cells and CD4+ T cells are associated with positive therapeutic response of neoadjuvant chemoimmunotherapy. B cell IgG subclasses IgG1 and IgG3 play a critical role in anti-tumor immune response in tumor lesion, and this process was driven by increased IL-21 protein secreted by infiltrated T follicular helper (Tfh) cells after neoadjuvant chemoimmunotherapy. Furthermore, we uncovered several critical events for positive clinical outcome, including the diminished activated TNFRSF4+ regulatory T cells (Tregs), increased LAMP3+ dendritic cells (DCs), high pre-therapy peripheral blood T-cell diversity, and the expansion of intratumoral CD4+ T clones and peripheral CD8+ T clones. In total, our comprehensive study of the single-cell profile of immune cells provide mechanistic insight of clinical responses and identified novel predictive factors and potential therapeutic targets for improving the efficiency of neoadjuvant chemoimmunotherapy in NSCLC.

scholarly journals Single-cell analysis of diverse immune phenotypes in malignant pleural effusion

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhong-Yin Huang ◽  
Ming-Ming Shao ◽  
Jian-Chu Zhang ◽  
Feng-Shuang Yi ◽  
Juan Du ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
B Cells ◽  
Pleural Effusion ◽  
Small Cell Lung Cancer ◽  
Single Cell ◽  
Immune Cells ◽  
Malignant Pleural Effusion ◽  
Small Cell ◽  
Small Cell Lung

AbstractThe complex interactions among different immune cells have important functions in the development of malignant pleural effusion (MPE). Here we perform single-cell RNA sequencing on 62,382 cells from MPE patients induced by non-small cell lung cancer to describe the composition, lineage, and functional states of infiltrating immune cells in MPE. Immune cells in MPE display a number of transcriptional signatures enriched for regulatory T cells, B cells, macrophages, and dendritic cells compared to corresponding counterparts in blood. Helper T, cytotoxic T, regulatory T, and T follicular helper cells express multiple immune checkpoints or costimulatory molecules. Cell-cell interaction analysis identifies regulatory B cells with more interactions with CD4+ T cells compared to CD8+ T cells. Macrophages are transcriptionally heterogeneous and conform to M2 polarization characteristics. In addition, immune cells in MPE show the general up-regulation of glycolytic pathways associated with the hypoxic microenvironment. These findings show a detailed atlas of immune cells in human MPE and enhance the understanding of potential diagnostic and therapeutic targets in advanced non-small cell lung cancer.

scholarly journals Publisher Correction: Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing

2018 ◽  
Vol 24 (10) ◽  
pp. 1628-1628 ◽  
Author(s):  
Xinyi Guo ◽  
Yuanyuan Zhang ◽  
Liangtao Zheng ◽  
Chunhong Zheng ◽  
Jintao Song ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Single Cell ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Single Cell Sequencing

Association of the T-cell receptor landscape with survival in non-small cell lung cancer.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 140-140 ◽  
Author(s):  
Alexandre Reuben ◽  
Rachel Gittelman ◽  
Jiexin Zhang ◽  
Kelly Quek ◽  
Luis M Vence ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Small Cell ◽  
Normal Lung ◽  
Small Cell Lung ◽  
Immune Microenvironment ◽  
Nsclc Patients

140 Background: Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types which respond best to immune checkpoint blockade, likely through its ability to enhance the anti-tumor T cell response. However, the lung is constantly exposed to the outside environment, which may result in a continuous state of inflammation targeting pathogens rather than tumor cells. Therefore, a greater understanding of the T cell receptor (TCR) landscape and phenotypes across normal lung and tumor is warranted. Methods: Here, we performed sequencing of the CDR3 variable region of the beta chain of the TCR as well as whole exome sequencing on peripheral blood, normal lung and tumor in 235 NSCLC patients. We further analyzed the immune microenvironment by Cytometry by Time-of-Flight (CyTOF) in 10 NSCLC patients with paired normal lung and tumor. Results: Comparison of the TCR repertoire showed 9% (up to 15%) of T cells were shared between normal lung and tumor, though the most dominant were generally shared (up to 95%). Interestingly, T cell clonality was higher in the normal lung than tumor in almost all patients (89%, p < 0.0001) suggesting potential differences in the ongoing immune response in different regions of the lung. A substantial number of non-synonymous exonic mutations (NSEM) were detected in tumors (average = 566 NSEM) but also in the normal lung (average = 156 NSEM), with many shared (up to 45.6%). CyTOF confirmed marked differences in the immune microenvironment, including higher frequency of VISTA+ antigen-presenting cells in the tumor (p = 0.04). Finally, analysis of clinicopathological attributes revealed a greater T cell diversity in the periphery in patients with increased overall survival (OS, p = 0.001), while patients with a more similar normal lung/tumor T cell repertoire showed decreased OS (p = 0.028). Conclusions: These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be lung-resident T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes, which highlights differences in the ongoing antigenic response within the lung.

Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing

2018 ◽  
Vol 24 (7) ◽  
pp. 978-985 ◽  
Author(s):  
Xinyi Guo ◽  
Yuanyuan Zhang ◽  
Liangtao Zheng ◽  
Chunhong Zheng ◽  
Jintao Song ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Single Cell ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Single Cell Sequencing

scholarly journals Expression of PD-1/PD-L1 and PD-L2 in peripheral T-cells from non-small cell lung cancer patients

Oncotarget ◽  
2017 ◽  
Vol 8 (60) ◽  
pp. 101994-102005 ◽  
Author(s):  
Oscar Arrieta ◽  
Edgar Montes-Servín ◽  
Juan-Manuel Hernandez-Martinez ◽  
Andrés F. Cardona ◽  
Eibar Casas-Ruiz ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cancer Patients ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancer Patients ◽  
Peripheral T Cells

scholarly journals Biomarkers and Gene Signatures to Predict Durable Response to Pembrolizumab in Non-Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3828
Author(s):  
Anello Marcello Poma ◽  
Rossella Bruno ◽  
Iacopo Pietrini ◽  
Greta Alì ◽  
Giulia Pasquini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Durable Response ◽  
Nsclc Patients

Pembrolizumab has been approved as first-line treatment for advanced Non-small cell lung cancer (NSCLC) patients with tumors expressing PD-L1 and in the absence of other targetable alterations. However, not all patients that meet these criteria have a durable benefit. In this monocentric study, we aimed at refining the selection of patients based on the expression of immune genes. Forty-six consecutive advanced NSCLC patients treated with pembrolizumab in first-line setting were enrolled. The expression levels of 770 genes involved in the regulation of the immune system was analysed by the nanoString system. PD-L1 expression was evaluated by immunohistochemistry. Patients with durable clinical benefit had a greater infiltration of cytotoxic cells, exhausted CD8, B-cells, CD45, T-cells, CD8 T-cells and NK cells. Immune cell scores such as CD8 T-cell and NK cell were good predictors of durable response with an AUC of 0.82. Among the immune cell markers, XCL1/2 showed the better performance in predicting durable benefit to pembrolizumab, with an AUC of 0.85. Additionally, CD8A, CD8B and EOMES showed a high specificity (>0.86) in identifying patients with a good response to treatment. In the same series, PD-L1 expression levels had an AUC of 0.61. The characterization of tumor microenvironment, even with the use of single markers, can improve patients’ selection for pembrolizumab treatment.

278 Phase I clinical trial evaluating the safety of ADP-A2M10 SPEAR T-cells in patients with MAGE-A10+ advanced non-small cell lung cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A303-A303
Author(s):  
George Blumenschein ◽  
Siddhartha Devarakonda ◽  
Melissa Johnson ◽  
Victor Moreno ◽  
Justin Gainor ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Antitumor Activity ◽  
Small Cell Lung Cancer ◽  
Dose Level ◽  
Cell Lung Cancer ◽  
Lentiviral Vector ◽  
Small Cell ◽  
Small Cell Lung ◽  
Human Dose

BackgroundADP-A2M10 SPEAR T-cells are genetically engineered autologous T-cells that express a high affinity MAGE-A10-specific T-cell receptor targeting MAGE-A10+tumors in the context of HLA-A*02. This trial is now complete (NCT02592577).MethodsThis first-in-human dose escalation trial utilized a modified 3+3 design to evaluate safety and antitumor activity. Eligible patients (pts) were HLA-A*02+ with advanced non-small cell lung cancer (NSCLC) expressing MAGE-A10. Pts underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Pts underwent lymphodepletion (LD) with varying doses/schedules of fludarabine (Flu) and cyclophosphamide (Cy) prior to receiving ADP-A2M10. ADP-A2M10 was administered at Dose Level (DL) 1= 0.1×109, DL2 0.5–1.2×109, and DL3/Expansion= 1.2–15×109 transduced cells.ResultsAs of Jan 10, 2020, 11 pts (6 male/5 female) with NSCLC (3 squamous cell, 7 adenocarcinoma, 1 adenosquamous) were treated. Five, 3 and 3 pts received cells at DL1, DL2, and DL3/Expansion, respectively. The most frequently reported adverse events ≥ Grade 3 were lymphopenia (11), leukopenia (9), neutropenia (8), anemia (6), thrombocytopenia (5), and hyponatremia (5). Three pts reported CRS (Grades 1, 2, and 4, respectively). One pt received the highest dose of LD (Flu 30 mg/m2 Day 1 4 and Cy 1800 mg/m2 Day 1–2) prior to a second infusion and had a partial response (PR). This pt subsequently developed aplastic anemia and died. Responses included: 1 pt – PR, 3 pts - stable disease, 2 pts – progressive disease, 1 pt - too early to determine, 4 pts - off-study prior to tumor assessment. SPEAR T-cells were detectable in peripheral blood from pts at each dose level, and in tumor tissue from pts at DL1 and DL3.ConclusionsADP-A2M10 SPEAR T-cells have shown acceptable safety and no evidence of toxicity related to off-target binding or alloreactivity. Given the minimal antitumor activity and the discovery that MAGE-A10 expression frequently overlaps with MAGE-A4 expression, the clinical program has closed. Several trials with SPEAR T-cells targeting MAGE-A4 are ongoing (https://bit.ly/35htsZK).Trial RegistrationNCT02592577Ethics ApprovalThe trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.

546 The differentiation status of systemic PD1+ CD8 T cells is associated with favorable outcome to PD1 blockade therapy in non small cell lung cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A582-A582
Author(s):  
Asma Khanniche ◽  
Ying Wang
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cd8 T Cells ◽  
Small Cell ◽  
Favorable Outcome ◽  
Small Cell Lung ◽  
Differentiation Status ◽  
Pd1 Blockade

BackgroundNon small cell lung cancer is one of the cancer types where Immune checkpoint blockade has demonstrated unprecedented clinical efficiency. However, only a fraction of patients benefit from such therapy; factors determining this response are yet to be elucidated. Here, we investigated whether the differentiation status of circulating CD8 T cells might be associated with outcome of PD1 blockade therapy in NSCLC.MethodsWe used multi-parameter flow cytometry to study CD8 T cell differentiation states in NSCLC patients at baseline and to examine the effects of blocking the PD1/PDL1 pathway on those cells.ResultsWe found that responders to PD1 blockade therapy has more peripheral PD1+ CD8 T cells with an early-like differentiated status at baseline and that this phenotype is associated with longer survival. Moreover, PD1 blockade induced reinvigoration is mostly observed in cells with this with an early-like differentiated status.ConclusionsAn early like differentiation status of peripheral CD8 T cells is associated with favorable outcome of PD1 blockade immunotherapy

scholarly journals Durvalumab and tremelimumab with or without stereotactic body radiation therapy in relapsed small cell lung cancer: a randomized phase II study

2020 ◽  
Vol 8 (2) ◽  
pp. e001302
Author(s):  
Suchita Pakkala ◽  
Kristin Higgins ◽  
Zhengjia Chen ◽  
Gabriel Sica ◽  
Conor Steuer ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Radiation Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Peripheral Blood ◽  
Stereotactic Body Radiation Therapy ◽  
Small Cell ◽  
Small Cell Lung ◽  
Stereotactic Body Radiation

BackgroundImmune checkpoint blockade (ICB) targeting programmed cell death protein 1 and cytotoxic T lymphocyte-associated protein 4 has achieved modest clinical activity as salvage therapy in relapsed small cell lung cancer (SCLC). We conducted this signal-finding study to assess the efficacy of ICB with or without radiation in relapsed SCLC.MethodsPatients with relapsed SCLC and ≤2 previous lines of therapy were randomized to (1) arm A: durvalumab (D) 1500 mg/tremelimumab (T) 75 mg (intravenously every 4 weeks without stereotactic body radiation therapy (SBRT)) or (2) arm B: immune-sensitizing SBRT to one selected tumor site (9 Gy × 3 fractions) followed by D/T. Treatment continued until progression or a maximum of 12 months. The co-primary endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). We evaluated circulating lymphocyte repertoire in serial peripheral blood samples and tumor infiltrating lymphocytes (TILs) from on-treatment biopsies as pharmacodynamic markers.ResultsEighteen patients were randomized to arms A and B (n=9 each): median age 70 years; 41.2% women. The median PFS and ORR were 2.1 months and 0% in arm A and 3.3 months and 28.6% in arm B. The median overall survival (OS) was 2.8 months in arm A and 5.7 months in arm B (p=0.3772). Pooled efficacy of D/T±SBRT in 15 Response evaluation criteria in solid tumors (RECIST) evaluable patients across both arms showed the best ORR in terms of partial response in 13.3%, stable disease in 26.6% and progressive disease in 60.0%; the overall median PFS and OS were 2.76 and 3.9 months. The most common adverse events were grade 1 fatigue (66%) and grade 1 elevated amylase (56%) in arm A, and grade 1 fatigue (56%) and pain (44%) in arm B. There was a significant increase in activated CD8(+)ICOS+ T cells (p=0.048) and a reduction in naïve T cells (p=0.0454) in peripheral blood following treatment, along with a significant amount of activated CD8+ICOS+ T cells in TILs from responders.ConclusionsThe D/T combination with and without SBRT was safe but did not show sufficient efficacy signal in relapsed SCLC. Changes in peripheral blood lymphocyte and TILs were consistent with an immunologic response.Trial registration numberNCT02701400.

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