Characterizing the T cell repertoire in lung squamous cell premalignancy and its association with lesion outcome.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 102-102
Author(s):  
Asaf Maoz ◽  
Carter Merenstein ◽  
Sarah Mazzilli ◽  
Joshua Campbell ◽  
Gang Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma ◽  
Premalignant Lesions ◽  
Rna Seq ◽  
Molecular Features ◽  
Mutational Burden ◽  
Tcr Repertoire ◽  
Tcr Diversity

102 Background: The immune response to frank malignancy has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical, pathological and molecular features. Methods: Endobronchial biopsies (n=294) and brushings (n=137) from high-risk subjects (n=50), undergoing lung cancer screening at approximately 1-year intervals via auto fluorescence bronchoscopy and CT, were profiled by RNA-Seq as part of the Pre-Cancer Genome Atlas (PCGA). We applied the TCR Repertoire Utilities for Solid Tissue/Tumor (TRUST) tool to identify TCR CDR3 sequences in the RNA-Seq data. We quantified the ratio of private (i.e., found in one patient only) and public (i.e. found in two or more patients) TCRs that are found in curated databases with known antigen specificities. We measured the correlation of TCR diversity with previously derived PML transcriptional signatures and molecular subtypes; and with mutational burden among a subset of biopsies (n=115) also profiled with whole exome sequencing. Results: We detected 40,421 unique TCR sequences, of which 3,396 (8.4%) were found in more than one sample and 1,057 (2.6%) were found in two or more patients (i.e. Public). TCRs with known antigen specificities were enriched among public TCRs (p < 0.001). In PMLs with a proliferative molecular subtype reflective of dysplasia (n=80), TCR diversity was decreased in PMLs that regressed versus PMLs that progressed (p=0.045). TCR diversity was negatively associated with a transcriptional signature of T-cell mediated immune activation (Spearman’s rho -0.26, p < 0.001) but was not associated with mutational burden. Conclusions: To our knowledge, this is the first characterization of the TCR repertoire associated with bronchial premalignant lesions. TCR diversity may help predict the efficacy of the host immune response to PMLs but it is not associated with mutational burden. Further studies are needed to leverage these findings and explore the potential for immunoprevention of PMLs.

scholarly journals Elevated T cell repertoire diversity is associated with progression of lung squamous cell premalignant lesions

2021 ◽  
Author(s):  
Asaf Maoz ◽  
Carter Merenstein ◽  
Yusuke Koga ◽  
Austin Potter ◽  
Adam C. Gower ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Squamous Cell ◽  
Molecular Subtype ◽  
Lung Squamous Cell Carcinoma ◽  
Premalignant Lesions ◽  
Rna Seq ◽  
Molecular Features ◽  
Tcr Repertoire ◽  
Tcr Diversity

AbstractObjectiveThe immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical, pathological, and molecular features.MethodsEndobronchial biopsies (n=295) and brushings (n=137) from high-risk subjects (n=50), undergoing lung cancer screening at approximately 1-year intervals via autofluorescence bronchoscopy and CT, were profiled by RNA-seq. We applied the TCR Repertoire Utilities for Solid Tissue/Tumor (TRUST) tool to the RNA-seq data to identify TCR CDR3 sequences across all samples. In the biopsies, we measured the correlation of TCR diversity with previously derived immune-associated PML transcriptional signatures and outcome. We also quantified the spatial and temporal distribution of shared and clonally expanded TCRs. Using the biopsies and brushes, the ratio of private (i.e., found in one patient only) and public (i.e., found in two or more patients) TCRs was quantified and the CDR3 sequences were compared to those found in curated databases with known antigen specificities.ResultsWe detected 39,303 unique TCR sequences across all samples. In PML biopsies, TCR diversity was negatively associated with a transcriptional signature of T-cell mediated immune activation (Spearman’s rho −0.34, p < 0.001) associated with PML outcome.Additionally, in lesions of the proliferative molecular subtype, TCR diversity was decreased in regressive versus progressive/persistent PMLs (p=0.045). Within each patient, TCRs were more likely to be shared between biopsies sampled at the same timepoint than biopsies sampled at the same anatomic location at different times. Clonally expanded TCRs, within a biopsied lesion, were more likely to be expanded at future time points than non-expanded clones. The majority of TCR sequences were found in a single sample, with only 3,396 (8.6%) found in more than one sample and 1,057 (2.7%) found in two or more patients (i.e. public), however, when compared to a public database of CDR3 sequences, 4,543 (11.6%) of TCRs were identified as public. TCRs with known antigen specificities were enriched among Public TCRs (p < 0.001).ConclusionsDecreased TCR diversity may reflect nascent immune responses that contribute to PML elimination. Further studies are needed to explore the potential for immunoprevention of PMLs.

scholarly journals Elevated T cell repertoire diversity is associated with progression of lung squamous cell premalignant lesions

2021 ◽  
Vol 9 (9) ◽  
pp. e002647
Author(s):  
Asaf Maoz ◽  
Carter Merenstein ◽  
Yusuke Koga ◽  
Austin Potter ◽  
Adam C Gower ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Squamous Cell ◽  
Molecular Subtype ◽  
Lung Squamous Cell Carcinoma ◽  
Premalignant Lesions ◽  
Rna Seq ◽  
Molecular Features ◽  
Tcr Repertoire ◽  
Tcr Diversity

ObjectiveThe immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical, pathological, and molecular features.MethodsEndobronchial biopsies (n=295) and brushings (n=137) from high-risk subjects (n=50), undergoing lung cancer screening at approximately 1-year intervals via autofluorescence bronchoscopy and CT, were profiled by RNA-seq. We applied the TCR Repertoire Utilities for Solid Tissue/Tumor tool to the RNA-seq data to identify TCR CDR3 sequences across all samples. In the biopsies, we measured the correlation of TCR diversity with previously derived immune-associated PML transcriptional signatures and PML outcome. We also quantified the spatial and temporal distribution of shared and clonally expanded TCRs. Using the biopsies and brushes, the ratio of private (ie, found in one patient only) and public (ie, found in two or more patients) TCRs was quantified, and the CDR3 sequences were compared with those found in curated databases with known antigen specificities.ResultsWe detected 39,303 unique TCR sequences across all samples. In PML biopsies, TCR diversity was negatively associated with a transcriptional signature of T cell mediated immune activation (p=4e-4) associated with PML outcome. Additionally, in lesions of the proliferative molecular subtype, TCR diversity was decreased in regressive versus progressive/persistent PMLs (p=0.045). Within each patient, TCRs were more likely to be shared between biopsies sampled at the same timepoint than biopsies sampled at the same anatomic location at different times. Clonally expanded TCRs, within a biopsied lesion, were more likely to be expanded at future time points than non-expanded clones. The majority of TCR sequences were found in a single sample, with only 3396 (8.6%) found in more than one sample and 1057 (2.7%) found in two or more patients (ie, public); however, when compared with a public database of CDR3 sequences, 4543 (11.6%) of TCRs were identified as public. TCRs with known antigen specificities were enriched among public TCRs (p<0.001).ConclusionsDecreased TCR diversity may reflect nascent immune responses that contribute to PML elimination. Further studies are needed to explore the potential for immunoprevention of PMLs.

scholarly journals Publisher Correction: Autophagy promotes growth of tumors with high mutational burden by inhibiting a T-cell immune response

Nature Cancer ◽  
2021 ◽  
Author(s):  
Laura Poillet-Perez ◽  
Daniel W. Sharp ◽  
Yang Yang ◽  
Saurabh V. Laddha ◽  
Maria Ibrahim ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Immune Response ◽  
Mutational Burden

scholarly journals Modelling the interplay between the CD4$$^{+}$$/CD8$$^{+}$$ T-cell ratio and the expression of MHC-I in tumours

2021 ◽  
Vol 83 (1) ◽  
Author(s):  
Christian John Hurry ◽  
Alexander Mozeika ◽  
Alessia Annibale
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Critical Level ◽  
Cell Infiltration ◽  
Cytotoxic T Cell ◽  
Mhc I ◽  
Cell Ratio ◽  
T Cell Infiltration ◽  
Immunological Mechanisms ◽  
Tcr Repertoire

AbstractDescribing the anti-tumour immune response as a series of cellular kinetic reactions from known immunological mechanisms, we create a mathematical model that shows the CD4$$^{+}$$ + /CD8$$^{+}$$ + T-cell ratio, T-cell infiltration and the expression of MHC-I to be interacting factors in tumour elimination. Methods from dynamical systems theory and non-equilibrium statistical mechanics are used to model the T-cell dependent anti-tumour immune response. Our model predicts a critical level of MHC-I expression which determines whether or not the tumour escapes the immune response. This critical level of MHC-I depends on the helper/cytotoxic T-cell ratio. However, our model also suggests that the immune system is robust against small changes in this ratio. We also find that T-cell infiltration and the specificity of the intra-tumour TCR repertoire will affect the critical MHC-I expression. Our work suggests that the functional form of the time evolution of MHC-I expression may explain the qualitative behaviour of tumour growth seen in patients.

scholarly journals TCR Repertoire Characterization for T Cells Expanded in Response to hRSV Infection in Mice Immunized with a Recombinant BCG Vaccine

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 233
Author(s):  
Emma Rey-Jurado ◽  
Karen Bohmwald ◽  
Hernán G. Correa ◽  
Alexis M. Kalergis
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Bcg Vaccine ◽  
Lung Damage ◽  
Cell Repertoire ◽  
Cell Immunity ◽  
Tcr Repertoire ◽  
Syncytial Virus

T cells play an essential role in the immune response against the human respiratory syncytial virus (hRSV). It has been described that both CD4+ and CD8+ T cells can contribute to the clearance of the virus during an infection. However, for some individuals, such an immune response can lead to an exacerbated and detrimental inflammatory response with high recruitment of neutrophils to the lungs. The receptor of most T cells is a heterodimer consisting of α and β chains (αβTCR) that upon antigen engagement induces the activation of these cells. The αβTCR molecule displays a broad sequence diversity that defines the T cell repertoire of an individual. In our laboratory, a recombinant Bacille Calmette–Guérin (BCG) vaccine expressing the nucleoprotein (N) of hRSV (rBCG-N-hRSV) was developed. Such a vaccine induces T cells with a Th1 polarized phenotype that promote the clearance of hRSV infection without causing inflammatory lung damage. Importantly, as part of this work, the T cell receptor (TCR) repertoire of T cells expanded after hRSV infection in naïve and rBCG-N-hRSV-immunized mice was characterized. A more diverse TCR repertoire was observed in the lungs from rBCG-N-hRSV-immunized as compared to unimmunized hRSV-infected mice, suggesting that vaccination with the recombinant rBCG-N-hRSV vaccine triggers the expansion of T cell populations that recognize more viral epitopes. Furthermore, differential expansion of certain TCRVβ chains was found for hRSV infection (TCRVβ+8.3 and TCRVβ+5.1,5.2) as compared to rBCG-N-hRSV vaccination (TCRVβ+11 and TCRVβ+12). Our findings contribute to better understanding the T cell response during hRSV infection, as well as the functioning of a vaccine that induces a protective T cell immunity against this virus.

scholarly journals Distinctive roles of syntaxin binding protein 4 and its action target, TP63, in lung squamous cell carcinoma: a theranostic study for the precision medicine

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Erkhem-Ochir Bilguun ◽  
Kyoichi Kaira ◽  
Reika Kawabata-Iwakawa ◽  
Susumu Rokudai ◽  
Kimihiro Shimizu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Multivariate Analysis ◽  
Cell Carcinoma ◽  
Precision Medicine ◽  
Squamous Cell ◽  
Binding Protein ◽  
Lung Squamous Cell Carcinoma ◽  
Rna Seq ◽  
Cox Regression Analysis ◽  
The Impact

Abstract Background Lung squamous cell carcinoma (LSCC) remains a challenging disease to treat, and further improvements in prognosis are dependent upon the identification of LSCC-specific therapeutic biomarkers and/or targets. We previously found that Syntaxin Binding Protein 4 (STXBP4) plays a crucial role in lesion growth and, therefore, clinical outcomes in LSCC patients through regulation of tumor protein p63 (TP63) ubiquitination. Methods To clarify the impact of STXBP4 and TP63 for LSCC therapeutics, we assessed relevance of these proteins to outcome of 144 LSCC patients and examined whether its action pathway is distinct from those of currently used drugs in in vitro experiments including RNA-seq analysis through comparison with the other putative exploratory targets and/or markers. Results Kaplan–Meier analysis revealed that, along with vascular endothelial growth factor receptor 2 (VEGFR2), STXBP4 expression signified a worse prognosis in LSCC patients, both in terms of overall survival (OS, p = 0.002) and disease-free survival (DFS, p = 0.041). These prognostic impacts of STXBP4 were confirmed in univariate Cox regression analysis, but not in the multivariate analysis. Whereas, TP63 (ΔNp63) closely related to OS (p = 0.013), and shown to be an independent prognostic factor for poor OS in the multivariate analysis (p = 0.0324). The action pathway of STXBP4 on suppression of TP63 (ΔNp63) was unique: Ingenuity pathway analysis using the knowledge database and our RNA-seq analysis in human LSCC cell lines indicated that 35 pathways were activated or inactivated in association with STXBP4, but the action pathway of STXBP4 was distinct from those of other current drug targets: STXBP4, TP63 and KDR (VEGFR2 gene) formed a cluster independent from other target genes of tumor protein p53 (TP53), tubulin beta 3 (TUBB3), stathmin 1 (STMN1) and cluster of differentiation 274 (CD274: programmed cell death 1 ligand 1, PD-L1). STXBP4 itself appeared not to be a potent predictive marker of individual drug response, but we found that TP63, main action target of STXBP4, might be involved in drug resistance mechanisms of LSCC. Conclusion STXBP4 and the action target, TP63, could afford a key to the development of precision medicine for LSCC patients.

scholarly journals From Tumor Mutational Burden to Blood T Cell Receptor: Looking for the Best Predictive Biomarker in Lung Cancer Treated with Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2974
Author(s):  
Andrea Sesma ◽  
Julián Pardo ◽  
Mara Cruellas ◽  
Eva M. Gálvez ◽  
Marta Gascón ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cell ◽  
T Cell Receptor ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Cell Receptor ◽  
Mutational Burden ◽  
Tcr Repertoire ◽  
Tumor Mutational Burden ◽  
Tumor Immunogenicity

Despite therapeutic advances, lung cancer (LC) is one of the leading causes of cancer morbidity and mortality worldwide. Recently, the treatment of advanced LC has experienced important changes in survival benefit due to immune checkpoint inhibitors (ICIs). However, overall response rates (ORR) remain low in unselected patients and a large proportion of patients undergo disease progression in the first weeks of treatment. Therefore, there is a need of biomarkers to identify patients who will benefit from ICIs. The programmed cell death ligand 1 (PD-L1) expression has been the first biomarker developed. However, its use as a robust predictive biomarker has been limited due to the variability of techniques used, with different antibodies and thresholds. In this context, tumor mutational burden (TMB) has emerged as an additional powerful biomarker based on the observation of successful response to ICIs in solid tumors with high TMB. TMB can be defined as the total number of nonsynonymous mutations per DNA megabases being a mechanism generating neoantigens conditioning the tumor immunogenicity and response to ICIs. However, the latest data provide conflicting results regarding its role as a biomarker. Moreover, considering the results of the recent data, the use of peripheral blood T cell receptor (TCR) repertoire could be a new predictive biomarker. This review summarises recent findings describing the clinical utility of TMB and TCRβ (TCRB) and concludes that immune, neontigen, and checkpoint targeted variables are required in combination for accurately identifying patients who most likely will benefit of ICIs.

Assessment of T-Cell Receptor Repertoire and Clonal Expansion in Peripheral T-Cell Lymphoma Using RNA-Seq Data

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1451-1451
Author(s):  
Chao Wang ◽  
Qiang Gong ◽  
Weiwei Zhang ◽  
Javeed Iqbal ◽  
Yang Hu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Lymphoma ◽  
Cell Receptor ◽  
T Cell Lymphoma ◽  
Rna Seq ◽  
Tcr Repertoire ◽  
T Cell Clonality ◽  
Cell Clonality

Abstract Introduction: Diversity of the T-cell receptor (TCR) repertoire reflects the initial V(D)J recombination events as shaped by selection by self and foreign antigens. Next generation sequencing is a powerful method for profiling the TCR repertoire, including sequences encoding complementarity-determining region 3 (CDR3). Peripheral T-cell lymphoma (PTCL) is a group of malignancies that originate from mature T-cells. T-cell clonality of PTCL is routinely evaluated with a PCR-based method to detect TCR gamma and less frequently beta chain rearrangements using genomic DNA. However, there are limitations with this approach, chief among which is the lack of sequence information. To date, the TCR repertoire of different subtypes of PTCL remains poorly defined. Objective: The purpose of this study was to determine the utility of RNA-seq for assessing T-cell clonality and analyzing the TCR usage in PTCL samples. Methods: We analyzed RNA-seq data from 30 angioimmunoblastic T-cell lymphoma (AITL), 23 Anaplastic large cell lymphoma (ALCL), 10 PTCL-NOS, and 17 NKCL. Data from naïve T cells, TFH cells, and T-effector cells (CD4+ CD45RA− TCRβ+ PD-1lo CXCR5lo PSGL-1hi) were obtained from publicly available resources. Referenced TCR and immunoglobulin transcripts according to the International ImMunoGeneTics Information System (IMGT) database were quantified by Kallisto software. We divided the pattern of Vβ (T-cell receptor beta variable region) into three categories: monoclonal (mono- or bi-allelic), oligoclonal (3-4 dominant clones), and polyclonal. CDR3 sequences were extracted by MiXCR program. PCR of the gamma chain using genomic DNA was utilized to validate the clonality of selected cases. Single nucleotide variants (SNVs) were called from aligned RNA-seq data using Samtools and VarScan 2 programs. Results: Analysis of RNA-seq data identified preferential usage of TCR-Vβ, Dβ (diversity region), and Jβ (joining region), length diversity of CDR3, and usage of nontemplated bases. Dominant clones could be identified by transcriptome sequencing in most cases of AITL (21/30), ALCL (14/23), and PTCL-NOS (7/10). Median CDR3 length is 42 nucleotides (nt) in normal T cells, 41 nt in ALCL, 48 nt in PTCL-NOS, and 44 nt in AITL. In 30 AITL samples, 20 showed monoclonal Vβ with a single peak, and 9 showed polyclonal Vβ. One case had two dominant clones with different CDR3, only one of which was in frame, implying biallelic rearrangements. As many as 3511 clones supported by at least four reads could be detected in polyclonal cases. In monoclonal cases, the dominant clone varied between 11.8% and 92.8% of TCR with Vβ rearrangements. TRBV 20-1, which is the most commonly used segment in normal T cells, is also frequently used in the dominant clones in AITL. The monoclonal AITL cases showed mutation of TET2, RHOA, DNMT3A or IDH2 whereas most of the polyclonal cases were negative or had low VAF mutation suggesting low or absent of tumor infiltrate in the specimen sequenced. There is no obvious correlation of any of the mutations with Vβ usage. Clonal B cell expansion was noted in some AITL samples. The occurrence of a preferential TRBV9 expansion in PTCL-NOS was striking. More than half of ALCL samples (14/23) showed expression of clonal Vβ, but 3/14 dominant clones were out-of-frame. γ chain expression was very low in cells expressing TCRαβ, but both expression levels and clonality were higher in TCRγδ expressing tumors. NKCL did not express significant levels of TCR Vβ or Vγ genes. Discussion/Interpretation: Transcriptome sequencing is a useful tool for understanding the TCR repertoire in T cell lymphoma and for detecting clonality for diagnosis. Clonal, often out-of-frame, Vβ transcripts are detectable in most ALCL cases and preferential TRBV9 usage is found in PTCL-NOS. Disclosures No relevant conflicts of interest to declare.

The T Cell Receptor (TCR) Repertoire Is a Key Determinant of the Tumour Microenvironment (TME) in Diffuse Large B Cell Lymphoma (DLBCL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3893-3893
Author(s):  
Colm Keane ◽  
Kimberly Jones ◽  
Clare Gould ◽  
David Hamm ◽  
Peter Wood ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
De Novo ◽  
T Cell Response ◽  
M2 Macrophages ◽  
Tcr Repertoire ◽  
Immune Score ◽  
The Relationship

Abstract Background: We have recently demonstrated that an 'immune score' is strongly and independently prognostic in de novo DLBCL treated with R-CHOP immuno-chemotherapy. The score quantifies the relative composition of immune effectors (T cells) and checkpoints (e.g. PD-1 axis molecules and M2 macrophages), as a measure of net anti-tumoral immunity within the TME. It is also known that a diverse TCR repertoire is a hallmark of a robust anti-HIV T cell immune response; conversely in metastatic melanoma treated with anti-PD-1 checkpoint blockade, narrow more clonal TCR repertoires are associated with favorable response. The relationship between the intra-tumoral TCR repertoire and the TME in DLBCL following R-CHOP immuno-chemotherapy is unknown. Methods High-throughput unbiased TCR β chain sequencing was performed on 116 nodal tissues (101 de novo DLBCL patients treated with R-CHOP with long-term follow-up including 8 EBV+DLBCL; and 15 age/gender matched healthy lymph nodes). Outcomes included measurement of productive uniques (a measure of the number of functional T cells with a distinct TCR rearrangement or 'richness'); entropy (a measure of TCR 'diversity'), 'clonality' (a measure of clonal expansions) and the 'maximal frequency' of the most highly expressed clone within tumor biopsies. Results were compared to digital quantification (by nanoString) of key immune effector and checkpoint genes within the TME, the immune score, malignant cell-of-origin (COO), R-IPI and patient survival. Results: First we compared the TCR repertoire in lymphomatous and healthy nodes. There was a marked increase in clonality, reduced diversity and high maximal frequency within DLBCL nodes relative to healthy nodal tissue (both p<0.0001), consistent with an abnormally narrow TCR repertoire of antigen-specific T cells. Next, we tested the relationship between TCR and the TME. Notably, there was modest (r=0.3-0.7) but highly significant (all p<0.001) positive correlations between both richness and diversity (but not clonality) with CD3/CD4/CD8 T cells, and a range of immune checkpoints including PD-L1, PD-L2, LAG-3, CSF-1 and TIM-3. These findings are strongly suggestive of an adaptive immune response, in which malignant B cells influence (i.e. 'adapt') the TME in an attempt to counter an effective anti-lymphoma T-cell response that is in part influenced by the breadth of the TCR repertoire. Then we investigated the TCR repertoire in the context of prognosis and overall survival (OS) following R-CHOP. There were no correlations between COO or R-IPI with any TCR parameter. However, the presence of a high maximal frequency in the tumour biopsy was associated with significantly inferior 5 year OS of 59% compared to 81% in patients without a high maximal frequency (p=0.03, Figure 1). As expected, the immune score stratified patients into highly disparate outcomes: high-score 5-year overall survival 96% versus 42% for low-score (p<0.0001). Interestingly, there were significant differences in the TCR repertoire between the two groups. There was a significant increase for both richness and diversity in high immune score lymphoma patients (p=0.015 and p=0.018 respectively). In keeping, clonality was not increased in high-immune score patients. The only samples associated with increased T cell clonality were those patients with very high levels of intratumoral EBV, potentially reflecting the latent viral antigens expressed by this lymphoma. In the group of patients with poor prognosis (5 year OS 59%), defined by high maximal frequency, the immune score stratified two groups with very different outcomes (5 year OS 90% vs. 30%, p=0.003). Conclusions: These findings indicate the TCR repertoire as a key parameter of the TME that the malignant B cell attempts to narrow. A broad TCR repertoire is associated with a good prognostic immune score (i.e. increased T cells relative to PD-1 axis molecules and M2 macrophages checkpoints) after R-CHOP immunoÐchemotherapy, whereas a more clonal T cell response is associated with significantly inferior outcome. Figure 1. Figure 1. Disclosures Hamm: Adaptive Biotech: Employment.

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