Publications by authors named "Justina X Caushi"

8 Publications

  • Page 1 of 1

Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers.

Nature 2021 08 21;596(7870):126-132. Epub 2021 Jul 21.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.

PD-1 blockade unleashes CD8 T cells, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a 'barcode' to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein-Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIT TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.
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http://dx.doi.org/10.1038/s41586-021-03752-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338555PMC
August 2021

Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses.

J Clin Invest 2021 05;131(10)

Bloomberg~Kimmel Institute for Cancer Immunotherapy.

BACKGROUNDRecent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.METHODSWe used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.RESULTSMemory CD4+ T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to monospecific CD4+ T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC.CONCLUSIONSOur data confirm, for what we believe is the first time, the existence of unique memory CD4+ T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients.FUNDINGNIH funding (U54CA260492, P30CA006973, P41EB028239, R01AI153349, R01AI145435-A1, R21AI149760, and U19A1088791) was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the National Institute of Biomedical Imaging and Bioengineering. The Bloomberg~Kimmel Institute for Cancer Immunotherapy, The Johns Hopkins University Provost, and The Bill and Melinda Gates Foundation provided funding for this study.
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http://dx.doi.org/10.1172/JCI146922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121515PMC
May 2021

Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non-Small Cell Lung Cancer.

Clin Cancer Res 2020 03 21;26(6):1327-1337. Epub 2019 Nov 21.

Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.

Purpose: Neoadjuvant PD-1 blockade is a promising treatment for resectable non-small cell lung cancer (NSCLC), yet immunologic mechanisms contributing to tumor regression and biomarkers of response are unknown. Using paired tumor/blood samples from a phase II clinical trial (NCT02259621), we explored whether the peripheral T-cell clonotypic dynamics can serve as a biomarker for response to neoadjuvant PD-1 blockade.

Experimental Design: T-cell receptor (TCR) sequencing was performed on serial peripheral blood, tumor, and normal lung samples from resectable NSCLC patients treated with neoadjuvant PD-1 blockade. We explored the temporal dynamics of the T-cell repertoire in the peripheral and tumoral compartments in response to neoadjuvant PD-1 blockade by using the TCR as a molecular barcode.

Results: Higher intratumoral TCR clonality was associated with reduced percent residual tumor at the time of surgery, and the TCR repertoire of tumors with major pathologic response (MPR; <10% residual tumor after neoadjuvant therapy) had a higher clonality and greater sharing of tumor-infiltrating clonotypes with the peripheral blood relative to tumors without MPR. Additionally, the posttreatment tumor bed of patients with MPR was enriched with T-cell clones that had peripherally expanded between weeks 2 and 4 after anti-PD-1 initiation and the intratumoral space occupied by these clonotypes was inversely correlated with percent residual tumor.

Conclusions: Our study suggests that exchange of T-cell clones between tumor and blood represents a key correlate of pathologic response to neoadjuvant immunotherapy and shows that the periphery may be a previously underappreciated originating compartment for effective antitumor immunity..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073288PMC
March 2020

The Mutation-Associated Neoantigen Functional Expansion of Specific T Cells (MANAFEST) Assay: A Sensitive Platform for Monitoring Antitumor Immunity.

Cancer Immunol Res 2018 08 12;6(8):888-899. Epub 2018 Jun 12.

The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Mutation-associated neoantigens (MANA) are a target of antitumor T-cell immunity. Sensitive, simple, and standardized assays are needed to assess the repertoire of functional MANA-specific T cells in oncology. Assays analyzing cytokine production such as ELISpot and intracellular cytokine staining have been useful but have limited sensitivity in assessing tumor-specific T-cell responses and do not analyze antigen-specific T-cell repertoires. The FEST (Functional Expansion of Specific T cells) assay described herein integrates T-cell receptor sequencing of short-term, peptide-stimulated cultures with a bioinformatic platform to identify antigen-specific clonotypic amplifications. This assay can be adapted for all types of antigens, including MANAs via tumor exome-guided prediction of MANAs. Following identification by the MANAFEST assay, the MANA-specific CDR3 sequence can be used as a molecular barcode to detect and monitor the dynamics of these clonotypes in blood, tumor, and normal tissue of patients receiving immunotherapy. MANAFEST is compatible with high-throughput routine clinical and lab practices. .
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072595PMC
August 2018

Neoadjuvant PD-1 Blockade in Resectable Lung Cancer.

N Engl J Med 2018 May 16;378(21):1976-1986. Epub 2018 Apr 16.

From the Bloomberg-Kimmel Institute for Cancer Immunotherapy and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore (P.M.F., K.N.S., V.A., T.R.C., M.Z., S.C.Y., S.B., R.J.B., J.N., K.A.M., F.V., H.G., J.Z., J.X.C., H.Y.C., J.-W.S., R.B.S., J.W., E.G., H.W., G.L.R., J.M.T., V.E.V., S.L.T., J.R.B., D.M.P.); Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine (J.E.C., M.D.H., D.R.J., M.J.V., N.R., Z.O., V.R., J.D.W., T.M.) and the Ludwig Collaborative (J.D.W., T.M.) - all in New York; the Parker Institute for Cancer Immunotherapy, San Francisco (J.D.W., T.M.); and Swim Across America Laboratory, Charlotte, NC (J.D.W., T.M.).

Background: Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade.

Methods: In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses.

Results: Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab.

Conclusions: Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood. (Funded by Cancer Research Institute-Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621 .).
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http://dx.doi.org/10.1056/NEJMoa1716078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223617PMC
May 2018

Quantifying the anti-tumor immune response in patients receiving immunotherapy.

Discov Med 2017 08;24(130):59-68

The Bloomberg-Kimmel Institute for Cancer Immunotherapy, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

The use of immunotherapy in the treatment of cancer has resulted in a paradigm shift in clinical outcomes and in the correlative biomarkers that are most useful to evaluate in cancer patients. While several immunotherapeutic approaches have shown great promise, and several checkpoint inhibitors have been approved in the first and second line setting for multiple cancer types, major challenges remain in identifying the population of patients most likely to respond and in accurately monitoring clinical response while patients are receiving treatment. To best evaluate these prognostic and correlative parameters, the relationship between the anti-tumor immune response and treatment response should be evaluated. Sensitive and specific immune assays, therefore, need to be employed in patients receiving immunotherapy treatment. This review explores some of the current immunotherapies being assessed in cancer patients and describes the experimental tools available for monitoring the anti-tumor response prior to treatment or in patients receiving treatment. Studies of the correlation between these responses, as determined by these experimental assays, and response to immunotherapy should be performed to better select patients who will likely benefit from the different available immunotherapeutic treatments, to select the appropriate treatment approach, and to carefully monitor the response while on therapy.
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August 2017

Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening.

Cell 2017 Jul;170(3):577-592.e10

Novartis Institutes for Biomedical Research, Oncology Disease Area, Basel 4002, Switzerland; Cambridge, MA 02139, USA; and Emeryville, CA 94608, USA.

Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines. We describe findings of this screen, outlining the classes of cancer dependency genes and their relationships to genetic, expression, and lineage features. In addition, we describe robust gene-interaction networks recapitulating both protein complexes and functional cooperation among complexes and pathways. This dataset along with a web portal is provided to the community to assist in the discovery and translation of new therapeutic approaches for cancer.
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http://dx.doi.org/10.1016/j.cell.2017.07.005DOI Listing
July 2017

Studying clonal dynamics in response to cancer therapy using high-complexity barcoding.

Nat Med 2015 May 13;21(5):440-8. Epub 2015 Apr 13.

Oncology Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.

Resistance to cancer therapies presents a significant clinical challenge. Recent studies have revealed intratumoral heterogeneity as a source of therapeutic resistance. However, it is unclear whether resistance is driven predominantly by pre-existing or de novo alterations, in part because of the resolution limits of next-generation sequencing. To address this, we developed a high-complexity barcode library, ClonTracer, which enables the high-resolution tracking of more than 1 million cancer cells under drug treatment. In two clinically relevant models, ClonTracer studies showed that the majority of resistant clones were part of small, pre-existing subpopulations that selectively escaped under therapeutic challenge. Moreover, the ClonTracer approach enabled quantitative assessment of the ability of combination treatments to suppress resistant clones. These findings suggest that resistant clones are present before treatment, which would make up-front therapeutic combinations that target non-overlapping resistance a preferred approach. Thus, ClonTracer barcoding may be a valuable tool for optimizing therapeutic regimens with the goal of curative combination therapies for cancer.
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http://dx.doi.org/10.1038/nm.3841DOI Listing
May 2015
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