Characterization of γδ T cells in patients with non-small cell lung cancer

ABSTRACTSingle cell RNA-seq has enabled high-resolution characterization of molecular signatures of tumor-infiltrating lymphocytes. However, analyses at the transcript isoform level are rarely reported. As alternative splicing is critical to T cell differentiation and activation, here we proposed a computational method named as IDEA to comprehensively detect and annotate differentially used isoforms across cell subtypes. We applied IDEA on a scRNA-seq dataset of 12,346 T cells from non-small cell lung cancer. We found most genes tend to dominantly express one isoform in single T cells, enabling typing T cells according to the isotypes given a gene. Isotype analysis suggested that tumor-infiltrating T cells significantly preferred specific isotypes for 245 genes in CD8+ T cells and 456 genes in CD4+ T cells. Functional annotation suggests that the preferred isoforms involved in coding/non-coding switches, transcription start site changes, gains/losses of domains and subcellular translocation. Clonal analysis revealed that isoform switching occurred during T cell activation/differentiation. Our analysis provides precise characterization of the molecular events in tumor-infiltrating T cells and sheds new lights into the regulatory mechanisms of tumor-infiltrating T cells.

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

Nature Medicine ◽

10.1038/s41591-018-0045-3 ◽

2018 ◽

Vol 24 (7) ◽

pp. 978-985 ◽

Cited By ~ 231

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

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

Cancers ◽

10.3390/cancers13153828 ◽

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.

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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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0278 ◽

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.

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Real World Characterization of Advanced Non-Small Cell Lung Cancer in Never Smokers by Actionable Mutation Status

Clinical Lung Cancer ◽

10.1016/j.cllc.2021.01.013 ◽

2021 ◽

Author(s):

Kathleen Kerrigan ◽

Xuechen Wang ◽

Benjamin Haaland ◽

Blythe Adamson ◽

Shiven Patel ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Real World ◽

Small Cell ◽

Small Cell Lung ◽

Mutation Status ◽

Never Smokers

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P70.03 Molecular Characterization of AKT1 Gene in East Asian Non-Small Cell Lung Cancer Patients

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.1014 ◽

2021 ◽

Vol 16 (3) ◽

pp. S563

Author(s):

Q. Shen ◽

C. Xu ◽

W. Wang ◽

X. Du ◽

D. Wang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Patients ◽

Molecular Characterization ◽

Cell Lung Cancer ◽

East Asian ◽

Small Cell ◽

Small Cell Lung ◽

Lung Cancer Patients

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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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0546 ◽

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

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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001302 ◽

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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