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.

scholarly journals Characterization of Circulating T Cell Receptor Repertoire Provides Information about Clinical Outcome after PD-1 Blockade in Advanced Non-Small Cell Lung Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2950
Author(s):  
Ning Dong ◽  
Andrea Moreno-Manuel ◽  
Silvia Calabuig-Fariñas ◽  
Sandra Gallach ◽  
Feiyu Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Clinical Outcome ◽  
Small Cell Lung Cancer ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Jaccard Similarity ◽  
Nsclc Patients

Despite the success of immunotherapies in lung cancer, development of new biomarkers for patient selection is urgently needed. This study aims to explore minimally invasive approaches to characterize circulating T cell receptor beta chain (TCR-β) repertoire in a cohort of advanced non-small cell lung cancer (NSCLC) patients treated with first-line pembrolizumab. Peripheral blood samples were obtained at two time points: i) pretreatment (PRE) and ii) first response assessment (FR). Next-generation sequencing (NGS) was used to analyze the hypervariable complementary determining region 3 (CDR3) of TCR-β chain. Richness, evenness, convergence, and Jaccard similarity indexes plus variable (V) and joining (J)-gene usage were studied. Our results revealed that increased richness during treatment was associated with durable clinical benefit (DCB; p = 0.046), longer progression-free survival (PFS; p = 0.007) and overall survival (OS; p = 0.05). Patients with Jaccard similarity index ≥0.0605 between PRE and FR samples showed improved PFS (p = 0.021). Higher TRBV20-1 PRE usage was associated with DCB (p = 0.027). TRBV20-1 levels ≥9.14% in PRE and ≥9.02% in FR significantly increased PFS (p = 0.025 and p = 0.016) and OS (p = 0.035 and p = 0.018). Overall, analysis of circulating TCR-β repertoire may provide information about the immune response in anti-PD-1 treated NSCLC patients; in this scenario, it can also offer important information about the clinical outcome.

scholarly journals Tumor Immune Microenvironment Characteristics and Their Prognostic Value in Non-Small-Cell Lung Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Dan Su ◽  
Gao Wu ◽  
Ran Xiong ◽  
Xiangxiang Sun ◽  
Meiqing Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Flow Cytometry ◽  
T Cells ◽  
Immune Cells ◽  
Small Cell ◽  
Normal Lung ◽  
Small Cell Lung ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Nsclc Patients

IntroductionCancer progression is determined not only by the malignant behavior of tumors but also by the immune microenvironment. The tumor immune microenvironment also plays a pivotal role in determining the clinical response of non-small-cell lung cancer (NSCLC) to immunotherapies. To understand the possible mechanisms and explore new targets in lung cancer immunotherapy, we characterized the immune profiles in NSCLC patients.MethodsSeventy-one NSCLC patients who underwent radical resection were selected. The immune cell composition in paired tumor and adjacent normal lung tissues was tested by flow cytometry. The associations of tumor immune microenvironment characteristics with clinicopathological factors and overall survival were analyzed. Kaplan–Meier curves and Cox proportional hazards models were used to determine differences in survival.ResultsCompared with adjacent normal lung tissues, an increased proportion of CD45+ hematopoietic-derived cells, CD4+ T cell subtypes, Tregs and B cells was observed in tumor samples with a reduced frequency of myeloid cell populations. There was no significant increase in total CD8+ T cells, but both PD1+ and CD38+ CD8+ T cells were significantly enriched in tumor samples and statistically significantly associated with tumor size. In addition, positive CD38 expression was highly correlated with PD1 positivity. A high proportion of CD8+ T cells and a low percentage of PD1+ CD8+ T cells were statistically significantly associated with better survival in stage II and III patients, whereas a low frequency of CD38+ CD8+ T cells was statistically significantly associated with better survival in all patients and identified as an independent prognostic factor (p=0.049).ConclusionWe profiled the immune cells in the tumor tissues of NSCLC patients using flow cytometry. The results revealed significant enrichment of infiltrating immune cells. A strong correlation was identified between CD38 and PD-1 expression on CD8+ T cells in tumors. CD8+ T cells and their subtypes play a critical role in the prediction of prognosis.

scholarly journals T-Cell Receptor Profiling and Prognosis After Stereotactic Body Radiation Therapy For Stage I Non-Small-Cell Lung Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Lirong Wu ◽  
Jun Zhu ◽  
Nils-Petter Rudqvist ◽  
James Welsh ◽  
Percy Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
T Cell Receptor ◽  
Shannon Entropy ◽  
Cell Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tcr Repertoire ◽  
Before And After

Radiotherapy is known to influence immune function, including T cell receptor (TCR) repertoire. We evaluated the TCR repertoire before and after stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) and explored correlations between TCR indexes and distant failure after SBRT. TCR repertoires were analyzed in peripheral blood mononuclear cells (PBMCs) collected before and after SBRT from 19 patients. TCR combinational diversity in V and J genes was assessed with multiplex PCR of genomic DNA from PBMCs and tested for associations with clinical response. All patients received definitive SBRT to a biologically effective dose of &gt;=100 Gy. The number of unique TCR clones was decreased after SBRT versus before, but clonality and the Shannon Entropy did not change. Four patients (21%) developed distant metastases after SBRT (median 7 months); those patients had lower Shannon Entropy in post-SBRT samples than patients without metastasis. Patients with a low change in Shannon Entropy from before to after SBRT [(post-SBRT Shannon Entropy minus baseline Shannon)/(baseline Shannon) * 100] had poorer metastasis-free survival than those with high change in Shannon Entropy (P&lt;0.001). Frequencies in V/J gene fragment expression in the TCR β chain were also different for patients with or without metastases (two V fragments in baseline samples and 2 J and 9 V fragments in post-treatment samples). This comprehensive analysis of immune status before and after SBRT showed that quantitative assessments of TCRs can help evaluate prognosis in early-stage NSCLC.

scholarly journals 286 Sex differences in the transcriptional profiles of mucosal-associated invariant T cells in neoadjuvant anti-PD-1 treated non-small cell lung cancer (NSCLC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A310-A310
Author(s):  
Poromendro Burman ◽  
Boyang Zhang ◽  
Zhicheng Ji ◽  
Justina Caushi ◽  
Frank Housseau ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Normal Lung ◽  
Small Cell Lung ◽  
Mait Cells ◽  
Invariant T Cells

BackgroundMucosal Associated Invariant T Cells (MAIT cells) are unconventional T cells that recognize vitamin B metabolites derived from bacteria and are mainly present in mucosal tissues and peripheral blood.1 Their activation by T Cell Receptor (TCR)-dependent and -independent pathways can result in effector function that can either promote or inhibit cytotoxic effects.2 MAIT cells are known to be involved in the pathogenesis of multiple diseases that involve mucosal tissues, such as non-small cell lung cancer (NSCLC).2 Recently, studies have shown that disparate outcomes to SARS-CoV-2-infection between males and females may involve a differential activation of MAIT cells in the lung mucosa.3 It is therefore conceivable to hypothesize that sex differences of MAIT cells in NSCLC may also impact outcome, however their involvement in progression and subsequent treatment response of NSCLC has never been explored.MethodsTo study the transcriptional program of MAIT cells in NSCLC as a function of sex, peripheral blood and tissue biospecimens were obtained from the first-in-human clinical trial of neoadjuvant anti-PD-1 (nivolumab) in resectable non-small cell lung cancer; NCT02259621.4 Coupled single-cell RNAseq/TCRseq was performed on tumor infiltrating lymphocytes (TIL), paired adjacent normal lung, and tumor-draining lymph nodes (TDLN). MAIT cells were identified by expression of SLC4A10 and the invariant TRAV1-2 and TRAJ33/12/20 TCR. Computational analysis revealed 4 distinct MAIT cell clusters and differentially expressed genes in the tumors and healthy normal lung of males as compared to females.ResultsIn MAIT cells from females, we found upregulation of CD8A, GNLY, and NKG7 genes. These genes are involved with T cell activation and cytolytic function, suggesting that the activation of these genes in MAIT cells could be contributing towards their cytolytic activity in females. In MAIT cells from males, we found upregulation of PDE3B and PCBP2 genes, which are known to be involved with immunosuppression and downregulation of cytotoxic T lymphocyte (CTL) responses. These findings were consistent in the healthy normal lung, suggesting these transcriptional programs may be due to the normal lung biology and not necessarily a byproduct of carcinogenesis.ConclusionsThese results highlight the potential for dual characteristics of MAIT cells in neoadjuvant anti-PD-1-treated NSCLCs and provide an important foundation in our study of the often dichotomous responses between males and females to immunotherapy. Future analyses will focus on the interplay of MAIT cells with other cells in the tumor microenvironment (TME) as a function of immunotherapy treatment and clinical response.ReferencesChen Z, Wang H, D’Souza C, et al. Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals. Mucosal Immunol 2017;10:58–68.Wen X, Zhang X, et al. Title of article: mucosal-associated invariant T cells in lung cancers. Elsevier 2021;94.Yu C, Littleton S, et al. Mucosal-associated invariant T cell responses differ by sex in COVID-19. CellPress 2021;2:755–772.Caushi JX, Zhang J, Ji Z, et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature 2021.Ethics ApprovalThis study was approved by the Institutional Review Boards (IRB) at Johns Hopkins University (JHU) and Memorial Sloan Kettering Cancer Center and was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The patients described in this study provided written informed consent.

scholarly journals The Effect of Smoking on the Immune Microenvironment and Immunogenicity and Its Relationship With the Prognosis of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Yueqin Sun ◽  
Qi Yang ◽  
Jie Shen ◽  
Ting Wei ◽  
Weitao Shen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Smoking Status ◽  
Small Cell ◽  
Small Cell Lung ◽  
Immune Microenvironment ◽  
Smoking Group ◽  
Nsclc Patients

Background: The emergence of immune checkpoint inhibitors (ICIs) has opened a new chapter for the treatment of non-small cell lung cancer (NSCLC), and the best beneficiaries of ICI treatment are still being explored. Smoking status has been repeatedly confirmed to affect the efficacy of ICIs in NSCLC patients, but the specific mechanism is still unclear.Methods: We performed analysis on the Memorial Sloan Kettering Cancer Center (MSKCC) clinical NSCLC cohort receiving ICI treatment, The Cancer Genome Atlas (TCGA) Pan-Lung Cancer cohort, and Gene Expression Omnibus (GEO) database GSE41271 lung cancer cohort that did not receive ICI treatment, including survival prognosis, gene mutation, copy number variation, immunogenicity, and immune microenvironment, and explored the impact of smoking status on the prognosis of NSCLC patients treated with ICIs and possible mechanism. In addition, 8 fresh NSCLC surgical tissue samples were collected for mass cytometry (CyTOF) experiments to further characterize the immune characteristics and verify the mechanism.Result: Through the analysis of the clinical data of the NSCLC cohort treated with ICIs in MSKCC, it was found that the smokers in NSCLC receiving ICI treatment had a longer progression-free survival (HR: 0.69, 95% CI: 0.49–0.97, p = 0.031) than those who never smoked. Further analysis of the TCGA and GEO validation cohorts found that the differences in prognosis between different groups may be related to the smoking group’s higher immunogenicity, higher gene mutations, and stronger immune microenvironment. The results of the CyTOF experiment further found that the immune microenvironment of smoking group was characterized by higher expression of immune positive regulatory chemokine, and higher abundance of immune activated cells, including follicular helper CD4+ T cells, gamma delta CD4+ T cells, activated DC, and activated CD8+ T cells. In contrast, the immune microenvironment of non-smoking group was significantly enriched for immunosuppressive related cells, including regulatory T cells and M2 macrophages. Finally, we also found highly enriched CD45RAhighCD4+ T cells and CD45RAhighCD8+ T cells in the non-smoking group.Conclusion: Our research results suggest that among NSCLC patients receiving ICI treatment, the stronger immunogenicity and activated immune microenvironment of the smoking group make their prognosis better.

The effect of different dose and sites of irradiation on lymphocyte subsets in peripheral blood of patients with lung cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21032-e21032
Author(s):  
Xiaotong Duan ◽  
Xiaoxia Zhu
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Peripheral Blood ◽  
Lymphocyte Subsets ◽  
Small Cell ◽  
Small Cell Lung ◽  
Thoracic Radiation ◽  
Nsclc Patients

e21032 Background: To explore the effect of different radiation doses and sites on systemic immunity in patients with lung cancer by detecting the changes in the percentage of lymphocyte subsets in peripheral blood before and after radiotherapy. Methods: Peripheral blood in 48 patients with lung cancer receiving radiotherapy were collected (before, during and after radiation), and the lymphocyte subsets as follow were examined: total T cell (CD3+), CD4+T cell, CD8+T cell, CD3+CD4+/CD3+CD8+, NK cell, memory T-helper cell subpopulation (CD4+ CD45RO+), CD4+ naïve T-cell subset (CD4+CD45RA+), cytotoxic T cell (CD8+CD28+), IL-2 receptor α(CD25+), B cells (CD3-CD19+), regulatory T cells (CD4+CD25+). The results were statistically analyzed with unpaired Student's t-test using GraphPrism6 software. Results: Among non-small cell lung cancer (NSCLC) patients treated with thoracic radiation (n = 21), B cells in patients receiving 20Gy/10F (P = 0.0072), 40Gy/ 20F (P = 0.0001), 60Gy/30F (P = 0.0002) irradiation were significantly lower than that before radiotherapy. However, CD4+ naïve T-cells decreased significantly at each dose point compared with that before radiotherapy, P values were 0.0394, 0.0081 and 0.0007, respectively. NK cells after completion of 60Gy/30F irradiation were distinctly lower than those after receiving 20Gy/10F of radiotherapy (P = 0.0278), and no significant difference was found in other immune cell subsets. Patients with small cell lung cancer (n = 6) who underwent thoracic radiation showed a similar trend of changes in B cells. However, the CD4+CD45RA+ subset decreased evidently after completing radiation compared with that after 10 fractions of irradiation (P = 0.0390). The NSCLC patients (n = 4) who received radiation for bone metastases (regimen: 36Gy/12F) had evidently lower B cells (CD3-CD19+) at the end of radiotherapy than that at the start of radiotherapy (P = 0.0286). Patients with NSCLC (n = 10) who received brain radiation (regimen: 40Gy/20F for whole brain, 54-56Gy/20F for multiple brain metastases) had a significantly reduced CD4+CD45RA+ subsets after finishing radiation (20F) compared with those after 10 fraction of radiation (P = 0.0497). The changes of other subsets were not statistically significant. Conclusions: The effect of radiation in different sites and doses on peripheral blood lymphocyte subsets is not identical.It is urgent to expand the sample size to explore the law for the optimization of radiation combined with immunotherapy.Funding: 81972853, 81572279, 2016J004, LC2019ZD009, 2018CR033

scholarly journals Deep Sequencing of T-Cell Receptors for Monitoring Peripheral CD8+ T Cells in Chinese Advanced Non–Small-Cell Lung Cancer Patients Treated With the Anti–PD-L1 Antibody

2021 ◽  
Vol 8 ◽  
Author(s):  
Jin Sheng ◽  
Huadi Wang ◽  
Xiao Liu ◽  
Yunyun Deng ◽  
Yingying Yu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Deep Sequencing ◽  
T Cell Receptors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tcr Repertoire ◽  
Response Group ◽  
Nsclc Patients

Background: Atezolizumab, a high-affinity engineered human anti–PD-L1 antibody, has produced a clinical benefit for patients with advanced non–small-cell lung cancer (NSCLC). However, associated with T-cell regulation, the immunomodulatory effect of PD-L1 blockade and its biomarker in peripheral immunity remains elusive.Methods: In a prospective cohort with 12 Chinese advanced NSCLC patients who received atezolizumab 1,200 mg every 3 weeks as a second-line treatment, blood samples were obtained before and 6 weeks after atezolizumab initiation, and when disease progression was confirmed. Patients were classified into a response or progression group according to response evaluation criteria in solid tumors (RECIST) 1.1. Fresh peripheral blood mononuclear cells (PBMCs) from patients were stained with antihuman CD3, CD8, and PD-1 antibodies for flow cytometry analysis. T-cell receptor (TCR)-β chains of CD8+ T cells were analyzed by next-generation sequencing (NGS) at the deep level. Diversity, clonality, and similarity of TCR have been calculated before and after treatment in both groups.Results: Clonal expansion with high PD-1 expression was detected in all patients’ peripheral CD8+ T cells before the treatment of atezolizumab. Unlike the progression group, the diversity of TCR repertoire and singletons in the TCRβ pool increased over time with atezolizumab administration, and the TCR repertoire dynamically changes in the response group. The percentage of CD8+ PD-1high terminal exhausted T cells declined in the response group after the PD-L1 blockade. Two patterns of TCR changes among patients who received PD-L1–targeted immunotherapy were observed.Conclusions: Deep sequencing of the T-cell receptors confirmed the existence of CD8+ PD-1high T cells with an exhaustion phenotype in Chinese NSCLC patients. Our study demonstrated that efficient anti–PD-L1 therapy could reshape the TCR repertoire for antitumor patients. Furthermore, singleton frequency may help us select patients who are sensitive to anti–PD-L1 immunotherapy.

Abstract 4159: Characterization of the T-cell receptor (TCR) repertoire in extensive disease small cell lung cancer (ED SCLC)

2016 ◽  
Author(s):  
Maen Hussein ◽  
Sharon Wilks ◽  
Marc Monte ◽  
Donald A. Richards ◽  
Jerome H. Goldschmidt ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Extensive Disease ◽  
Tcr Repertoire
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