https://orcid.org/0000-0003-4510-0382
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ABSTRACT
Background
A better understanding of T cells in lung cancer and their distribution across tumor-adjacent lungs and peripheral blood is needed to improve efficacy and minimize toxicity from immunotherapy to lung cancer patients.
Methods
Here, we performed CDR3β TCR sequencing of 136 samples from 20 patients with early-stage NSCLC including peripheral blood mononuclear cells, tumors, tumor edges (<1 cm from tumor), as well as adjacent lungs 1 cm, 2 cm, 5 cm, and 10 cm away from the tumor to gain insight into the spatial heterogeneity of T cells across the lungs in patients with NSCLC. PD-L1, CD4, and CD8 expression was assessed using immunohistochemical staining, and genomic features were derived by targeted sequencing of 1,021 cancer-related genes. Multiplex immunohistochemistry against PD-1, CTLA4, LAG3, and TIM3 was performed on four patients to assess T cell exhaustion.
Results
Our study reveals a decreasing gradient in TIL Tumor Infiltrating Lymphocytes homology with tumor edge, adjacent lungs, and peripheral blood but no discernible distance-associated patterns of T cell trafficking within the adjacent lung itself. Furthermore, we show a decrease in pathogen-specific TCRs in regions with high T cell clonality and PD-L1 expression.
Conclusions
Exclusion in T exhaustion cells at play across the lungs of patients with NSCLC may potentially be the mechanism for lung cancer occurrence.
SUMMARY
What is already known on this topic – The immunomodulatory effects of the tumor microenvironment (TME) significantly impact the T cell repertoire resulting in different anti-tumor immune responses. Previous work by our group and others has highlighted intratumor heterogeneity in T cell clonality, spatial distribution, and diversity, as well as infiltration of bystander, and exhausted T cells in early-stage non-small-cell lung cancer (NSCLC). However, little is known about how TME impacts the T cell repertoire in distant or surrounding adjacent uninvolved lung tissue.
What this study adds – We used a step-wise approach to deconstruct the T cell repertoire architecture across six regions within NSCLC tumor tissue and the surrounding healthy lung tissue. T cell markers and repertoire metrics were compared across resected tissue from the tumor, tumor edge (<1 cm from tumor), and 1, 2, 5, and 10 cm away from the tumor across 20 lung adenocarcinoma patients in order to better understand the impact of the tumor on the T cell repertoire across the lungs.
How this study might affect research, practice, or policy – We found that the regions with the highest clonality also present the lowest number of predicted pathogen-specific TCRs. This lack of predicted pathogen-specific TCRs could suggest a higher probability of infiltration with tumor-specific TCRs. This study indicates that exclusion in T cells at play across the lungs of patients with NSCLC may be potentially the mechanism for lung cancer occurrence.
KEYWORDS:
Acknowledgments
We thank SAN VALLEY DIAGNOSTICS, Servicebio Co., and Suzhou Abcarta Medical Technology Co. for their assistance with IHC experiments.
Disclosure statement
No potential conflict of interest was reported by the authors.
Authors’ contributions
Qikang Hu, Jianjun Zhang, Xuefeng Xia, Xin Yi, Alexandre Reuben and Fenglei Yu: conception and design, acquisition of data, data analysis and interpretation, manuscript drafting, critical revision; statistical analyses. Meredith Frank, Liyan Ji, Qiongzhi He, Yingqian Zhang and Jianjun Zhang: manuscript drafting. Jianjun Zhang,Yin Yi, Alexandre Reuben and Fenglei Yu: conceived of the idea, supervised this project, and revised the manuscript. Meredith Frank, Liyan Ji, Qiongzhi He, Yingqian Zhang, Alexandre Reuben, Muyun Peng, Chen Chen and Xuefeng Xia: acquisition of data, data analysis, and interpretation. Qikang Hu, Meredith Frank, Yang Gao, Muyun Peng, Chen Chen, Liyan Ji: contributed reagents/materials/analysis tools. Fenglei Yu, Yang Gao: obtained funding.
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Second Xiangya Hospital Central South University (IRB: 2020084).
Consent for publication
All authors have read and approved the article.
Availability of data and material
The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary materials. All data generated during this study are included in this published article and its supplementary information files. All data in this study are available from the corresponding author with a reasonable request.
List of Abbreviations
| ACT | = | adoptive cell therapy |
| CDR3 | = | complementarities determining region 3 |
| ICB | = | immune checkpoint blockade |
| ICP | = | immune cells present |
| IMGT | = | ImMunoGeneTics |
| MOI | = | Morisita overlap index |
| NSCLC | = | non-small cell lung cancer |
| TIL | = | tumor infiltrating lymphocytes |
| TMB | = | Tumor mutational burden |
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2233399