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Comprehensive T cell repertoire characterization of non-small cell lung cancer.

ABSTRACT: Immunotherapy targeting T cells is increasingly utilized to treat solid tumors including non-small cell lung cancer (NSCLC). This requires a better understanding of the T cells in the lungs of patients with NSCLC. Here, we report T cell repertoire analysis in a cohort of 236 early-stage NSCLC patients. T cell repertoire attributes are associated with clinicopathologic features, mutational and immune landscape. A considerable proportion of the most prevalent T cells in tumors are also prevalent in the uninvolved tumor-adjacent lungs and appear specific to shared background mutations or viral infections. Patients with higher T cell repertoire homology between the tumor and uninvolved tumor-adjacent lung, suggesting a less tumor-focused T cell response, exhibit inferior survival. These findings indicate that a concise understanding of antigens and T cells in NSCLC is needed to improve therapeutic efficacy and reduce toxicity with immunotherapy, particularly adoptive T cell therapy.

SUBMITTER: Reuben A

PROVIDER: S-EPMC6992630 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Comprehensive T cell repertoire characterization of non-small cell lung cancer.

Reuben Alexandre A Zhang Jiexin J Chiou Shin-Heng SH Gittelman Rachel M RM Li Jun J Lee Won-Chul WC Fujimoto Junya J Behrens Carmen C Liu Xiaoke X Wang Feng F Quek Kelly K Wang Chunlin C Kheradmand Farrah F Chen Runzhe R Chow Chi-Wan CW Lin Heather H Bernatchez Chantale C Jalali Ali A Hu Xin X Wu Chang-Jiun CJ Eterovic Agda Karina AK Parra Edwin Roger ER Yusko Erik E Emerson Ryan R Benzeno Sharon S Vignali Marissa M Wu Xifeng X Ye Yuanqing Y Little Latasha D LD Gumbs Curtis C Mao Xizeng X Song Xingzhi X Tippen Samantha S Thornton Rebecca L RL Cascone Tina T Snyder Alexandra A Wargo Jennifer A JA Herbst Roy R Swisher Stephen S Kadara Humam H Moran Cesar C Kalhor Neda N Zhang Jianhua J Scheet Paul P Vaporciyan Ara A AA Sepesi Boris B Gibbons Don L DL Robins Harlan H Hwu Patrick P Heymach John V JV Sharma Padmanee P Allison James P JP Baladandayuthapani Veera V Lee Jack J JJ Davis Mark M MM Wistuba Ignacio I II Futreal P Andrew PA Zhang Jianjun J

Nature communications 20200130 1

Immunotherapy targeting T cells is increasingly utilized to treat solid tumors including non-small cell lung cancer (NSCLC). This requires a better understanding of the T cells in the lungs of patients with NSCLC. Here, we report T cell repertoire analysis in a cohort of 236 early-stage NSCLC patients. T cell repertoire attributes are associated with clinicopathologic features, mutational and immune landscape. A considerable proportion of the most prevalent T cells in tumors are also prevalent i ...[more]

PMID: 32001676

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Project description:BackgroundKirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes in non-small cell lung cancer (NSCLC). The administration of immunotherapy has demonstrated significant efficacy in prolonging the overall survival of patients with KRAS mutation in recent years. However, the efficacy of immunotherapy in KRAS mutant NSCLC is variable. Analysis of T cell receptor (TCR) repertoire may contribute to a better understanding of the mechanisms behind such differential outcomes.MethodsA total of 47 patients with KRAS mutant NSCLC were enrolled in this study. Deep sequencing of the TCR β chain complementarity-determining regions in tumor tissue and paired peripheral blood specimens was conducted. Comprehensive analysis of TCR repertoire metrics was performed with different KRAS mutation subtypes and concomitant mutations. Moreover, the associations between TCR repertoire metrics and tumor mutation burden (TMB), as well as programmed death-ligand 1 were explored, respectively.ResultsTCR repertoire metrics, including Shannon index, Clonality, and Morisita index (MOI), showed no significant differences among different KRAS mutation subtypes. The similar results were observed between patients with tumor protein p53 (TP53) mutation and those with wild-type TP53. In contrast, although no significant differences were found in Shannon index and Clonality, patients with KRAS/serine/threonine kinase 11 (STK11) comutation showed a significantly higher MOI compared to their STK11 wild-type counterparts (P=0.012). In addition, TCR repertoire metrics were neither associated with TMB nor programmed death-ligand 1 expression in KRAS mutant NSCLC.ConclusionsThis retrospective study comprehensively described the TCR repertoire in KRAS mutant NSCLC. A higher MOI represented more overlap of the TCR repertoire between tumor tissue and paired peripheral blood, indicating distinctive immunological features in NSCLC with KRAS/STK11 comutation.

Project description:IntroductionB cells, which have long been thought to be minor players in the development of anti-tumor responses, have been implicated as key players in lung cancer pathogenesis and response to checkpoint blockade in patients with lung cancer. Enrichment of late-stage plasma and memory cells in the tumor microenvironment has been shown in lung cancer, with the plasma cell repertoire existing on a functional spectrum with suppressive phenotypes correlating with outcome. B cell dynamics may be influenced by the inflammatory microenvironment observed in smokers and between LUAD and LUSC.MethodsHere, we show through high-dimensional deep phenotyping using mass cytometry (CyTOF), next generation RNA sequencing and multispectral immunofluorescence imaging (VECTRA Polaris) that key differences exist in the B cell repertoire between tumor and circulation in paired specimens from lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC).ResultsIn addition to the current literature, this study provides insight into the in-depth description of the B cell contexture in Non-Small Cell Lung Cancer (NSCLC) with reference to broad clinico-pathological parameters based on our analysis of 56 patients. Our findings reinforce the phenomenon of B-cell trafficking from distant circulatory compartments into the tumour microenvironment (TME). The circulatory repertoire shows a predilection toward plasma and memory phenotypes in LUAD however no major differences exist between LUAD and LUSC at the level of the TME. B cell repertoire, amongst other factors, may be influenced by the inflammatory burden in the TME and circulation, that is, smokers and non-smokers. We have further clearly demonstrated that the plasma cell repertoire exists on a functional spectrum in lung cancer, and that the suppressive regulatory arm of this axis may play a significant role in determining postoperative outcomes as well as following checkpoint blockade. This will require further long-term functional correlation.ConclusionB and Plasma cell repertoire is very diverse and heterogeneous across different tissue compartments in lung cancer. Smoking status associates with key differences in the immune milieu and the consequent inflammatory microenvironment is likely responsible for the functional and phenotypic spectrum we have seen in the plasma cell and B cell repertoire in this condition.

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Comprehensive T cell repertoire characterization of non-small cell lung cancer.

Publications

Comprehensive T cell repertoire characterization of non-small cell lung cancer.

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