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 >=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<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.

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

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 Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

2021 ◽  
Author(s):  
Ming Chen ◽  
Runzhe Chen ◽  
Ying Jin ◽  
Jun Li ◽  
Jiexin Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cell Receptor ◽  
Small Cell ◽  
Intratumor Heterogeneity ◽  
High Recurrence Rate ◽  
Small Cell Lung ◽  
Tcr Repertoire

Abstract Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry (IHC), we revealed a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC (LS-SCLC) tumors. Compared to localized non-small cell lung cancers (NSCLCs), LS-SCLCs had similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression were associated with longer overall survival (OS), while higher CNA burden were associated with shorter OS in patients with LS-SCLC.

A novel noninvasive biomarker based on peripheral PD-1posi CD8 T-cell receptor repertoire correlated with clinical outcomes to immunotherapy in non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14174-e14174
Author(s):  
Jie-Fei Han ◽  
Zhijie Wang ◽  
Hua Bai ◽  
Si Chen ◽  
Yuqi Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Cell Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Non Invasive ◽  
Tcr Repertoire ◽  
Tcr Diversity

e14174 Background: Although advances on exploration of biomarkers personalized the immune checkpoint blockades (ICBs) delivery, non-invasive blood-based approach remainsan intriguing area for further investigation.This study investigated the feasibility of peripheral isolated PD-1posiCD8T cell receptor (TCR) repertoire profiling in predicting the clinical outcomes of ICBs treatment for non-small cell lung cancer (NSCLC) patients. Methods: The study comprised two independent cohorts (A and B), ultimately recruiting total 40 from 51 patients with stage IIIB-IV NSCLCs who received anti-PD-1/PD-L1 therapy between March 14, 2017 and May 2, 2018. Peripheral blood samples of pre- and post-ICBs (the timepoint of first imaging evaluation) were prospectively collected, and PD-1posiCD8 T cells were isolated by flow cytometry for TCR sequencing. The diversity and clonality of the TCR repertoire were calculated for biomarker profiling. Cohort A (n = 25) was used as a training set for discovery of TCR diversity in the prediction of response to ICBs, and cohort B (n = 15) as a validation set. Progression-free survival (PFS) and response to ICBs treatment were correlated with TCR diversity and clonality. Results: In cohort A, patients with high pre-ICBs PD-1posiCD8 TCR diversity had longer PFS than those with low diversity (6.5 vs. 2.6 months, p = .045), which were substantially validated in cohort B. By using the incorporated set, pre-ICBs PD-1posiCD8 TCR diversity exhibited an optimal Youden's index of 0.81 with a sensitivity of 0.87 and a specificity of 0.94 in clarifying clinical response of ICBs (PR+SD vs. PD). Patients with increased PD-1posiCD8 TCR clonality demonstrated significantly improved PFS (7.3 vs. 2.7 months, p = .005) compared to those with decreased TCR clonality. Interestingly, two patients with initial pseudo-PD exhibited similar change of TCR clonality and expansion of dominant TCR clones with those with PR, but not PD. Conclusions: Peripheral PD-1posiCD8 TCR repertoire sequencing might be a promising non-invasive approach for selecting patients who could benefit from ICBs treatment, which guaranteed the further investigation and validation by larger cohorts.

scholarly journals Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ming Chen ◽  
Runzhe Chen ◽  
Ying Jin ◽  
Jun Li ◽  
Xin Hu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Copy Number ◽  
Small Cell ◽  
High Recurrence Rate ◽  
Copy Number Loss ◽  
Small Cell Lung ◽  
Tcr Repertoire

AbstractSmall-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC.

scholarly journals The evolution of T-cell receptor repertoire in different stages of non-small cell lung cancer

2020 ◽  
Author(s):  
Ziqi Jia ◽  
Yadong Wang ◽  
Xiaoying Yang ◽  
Pancheng Wu ◽  
Yanyu Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Development ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tcr Repertoire

Abstract Background The intricate relationship between the tumor and host was not well understood, and antigen-specific T cell is fundamental in understanding the interaction. TCR repertoire analysis which described TCR clonotypes and TCR numbers has shown that TCRs with high frequency was tumor-specific T cells, while others might be ‘bystander’ T cells within tumors. However, how these “expanded” tumor-specific T cells was selected during the tumor development was not clear. Methods We retrospectively analyzed TCR sequencing and mutation sequencing results from 144 non-small cell lung cancer (NSCLC) patients. Results A rich TCR repertoire comprising thousands of different TCR sequences was identified in all stages of NSCLC, with most TCR clonotypes presented at low frequency. Interestingly, Stage IV NSCLC tumors contain more expanded TCRs as compared to earlier stages, however, lymph node metastasis or tumor size had little impact on expanded TCRs. Moreover, accumulation of mutations did not significantly change the number of TCR clonotypes, however, EGFR mutant patients had significantly lower while KRAS mutant patients had significantly higher number of TCR clonotypes especially in terms of those “expanded” TCRs. Conclusions In summary, T cells in the tumor microenvironment were gradually activated with tumor development. Critical events such as distal metastases and generation of EGFR or KRAS mutations might be the major factors affecting the changing of tumor-specific T cells in the tumor microenvironment.

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.

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