Low T-cell Receptor Diversity, High Somatic Mutation Burden, and High Neoantigen Load as Predictors of Clinical Outcome in Muscle-invasive Bladder Cancer

Choudhury, Noura J.; Kiyotani, Kazuma; Yap, Kai Lee; Campanile, Alexa; Antic, Tatjana; Yew, Poh Yin; Steinberg, Gary D.; Park, Jae Hyun; Nakamura, Yusuke; O’Donnell, Peter H.

doi:10.1016/j.euf.2015.09.007

Cited by 66 publications

(73 citation statements)

References 22 publications

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“…27,31 Briefly, during the synthesis of cDNA from total RNA, we added 5 0 rapid amplification of cDNA end adapter using SMART cDNA library construction kit (Clontech, Mountain View, CA, USA). The TCRb was amplified by PCR using a reverse primer specific to the constant region and a forward primer for the SMART adapter.…”

Section: Tcr Sequencingmentioning

confidence: 99%

Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma

et al. 2017

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To investigate the link between the genomic landscape of cancer cells and immune microenvironment in tumor tissues, we characterized somatic mutations and tumor-infiltrating lymphocytes (TILs) in malignant pleural mesothelioma (MPM), including mutation/neoantigen load, spatial heterogeneity of somatic mutations of cancer cells and TILs (T-cell receptor b (TCRb) repertoire), and expression profiles of immunerelated genes using specimens of three different tumor sites (anterior, posterior, and diaphragm) obtained from six MPM patients. Integrated analysis identified the distinct patterns of somatic mutations and the immune microenvironment signatures both intratumorally and interindividually. MPM cases showed intratumoral heterogeneity in somatic mutations with unique TCRb clonotypes of TILs that were restricted to each tumor site, suggesting the presence of a neoantigen-related immune response. Correlation analyses showed that higher neoantigen load was significantly correlated with stronger clonal expansion of TILs (p D 0.048) and a higher expression level of an immune-associated cytolytic factor (PRF1 (p D 0.0041) in tumor tissues), suggesting that high neoantigen loads in tumor cells might promote expansion of functional tumor-specific T cells in the tumor bed. Our results collectively indicate that MPM tumors constitute a diverse heterogeneity in both the genomic landscape and immune microenvironment, and that mutation/neoantigen load may affect the immune microenvironment in MPM tissues.

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Section: Tcr Sequencingmentioning

confidence: 99%

Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma

et al. 2017

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“…We basically applied the similar concept to our TCR sequencing method [7,14], and modified it for BCR sequencing. Addition of 5′ RACE adapter at the 5′ end during cDNA synthesis from total RNA allows us to amplify each BCR isotype using a single forward common primer.…”

Section: Establishment Of Bcr Sequencing Platform Using Illumina Sequmentioning

confidence: 99%

“…The library preparation method was basically same as the TCR sequencing method we previously reported [7,14]. First-strand cDNA described above were used for BCR sequencing analysis.…”

Section: Library Preparation For Bcr Sequencingmentioning

confidence: 99%

Characterization of the B-cell receptor repertoires in peanut allergic subjects undergoing oral immunotherapy

Kiyotani

Yamaguchi

et al. 2017

J Hum Genet

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B-cell receptors (BCRs) play a critical role in adaptive immunity as they generate highly diverse immunoglobulin repertoires to recognize a wide variety of antigens. To better understand immune responses, it is critically important to establish a quantitative and rapid method to analyze BCR repertoire comprehensively. Here, we developed "Bcrip", a novel approach to characterize BCR repertoire by sequencing millions of BCR cDNA using next-generation sequencer. Using this method and quantitative real-time PCR, we analyzed expression levels and repertoires of BCRs in a total of 17 peanut allergic subjects' peripheral blood samples before and after receiving oral immunotherapy (OIT) or placebo. By our methods, we successfully identified all of variable (V), joining (J), and constant (C) regions, in an average of 79.1% of total reads and 99.6% of these VJC-mapped reads contained the C region corresponding to the isotypes that we aimed to analyze. In the 17 peanut allergic subjects' peripheral blood samples, we observed an oligoclonal enrichment of certain immunoglobulin heavy chain alpha (IGHA) and IGH gamma (IGHG) clones (P = 0.034 and P = 0.027, respectively) in peanut allergic subjects after OIT. This newly developed BCR sequencing and analysis method can be applied to investigate B-cell repertoires in various research areas, including food allergies as well as autoimmune and infectious diseases.

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“…Total RNA was extracted from tumor/PBMC samples using RNeasy mini kit (Qiagen, Valencia, CA, USA) and TCR sequencing was performed as previously described [17,19,23]. Briefly, we synthesized cDNA with 5' rapid amplification of end (5'-RACE) adapter using SMART cDNA library kit (Clontech Laboratories, Mountain View, CA, USA).…”

Section: Tcr Repertoire Analysismentioning

confidence: 99%

Sustained Oligoclonal T Cell Expansion Correlates with Durable Response to Immune Checkpoint Blockade in Lung Cancer

Olugbile¹,

Park²,

Szeto³

et al. 2017

J Cancer Sci Ther

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Purpose: Antibodies that target immune checkpoint molecules have demonstrated significant and durable clinical benefit through re-activation and proliferation of pre-existing tumor-infiltrating CD8 + T cells in a broad range of tumor types including lung cancer. Detailed characterization of T cell dynamics at clonal levels using nextgeneration T cell receptor (TCR) sequencing in large cohorts of lung cancer patients is yet reported. Methods:We performed TCR sequencing of peripheral blood samples (and some tumors) obtained from 27 lung cancer patients undergoing single/combined immune checkpoint blockade therapies. Results:In one responder, we found expansion of a single T cell clone (approximately 20% of the all TCR reads) in a metastatic subcutaneous lesion that showed pathologic complete response on day 17 of treatment. The same TCR CDR3 sequence was detected in 6.1% of TCR reads in the peripheral blood prior to treatment initiation and the expansion remained persistent in peripheral blood at 21.0% at week 10 and 24.3% at week 48. In other patients who showed durable response, we also found persistent oligoclonal T cell expansion in their peripheral blood which was not observed in non-responders even while they remained on therapy. Conclusion:We found sustained expansion of oligoclonal T cell clones in lung cancer patients who had durable response to immune checkpoint blockade. This suggests possible use of longitudinal TCR sequencing to assist clinical decision-making, assess synergism with other agents, and most importantly facilitate rational development of alternative treatment strategies for non-responders.

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Low T-cell Receptor Diversity, High Somatic Mutation Burden, and High Neoantigen Load as Predictors of Clinical Outcome in Muscle-invasive Bladder Cancer

Abstract: We discovered that clonal expansion of certain T cells in tumor tissue, possibly targeting cancer-specific antigens, contributes to prevention of bladder cancer recurrence.

Cited by 66 publications

References 22 publications

Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma

Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma

Characterization of the B-cell receptor repertoires in peanut allergic subjects undergoing oral immunotherapy

Sustained Oligoclonal T Cell Expansion Correlates with Durable Response to Immune Checkpoint Blockade in Lung Cancer

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