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Marrow-Infiltrating Regulatory T Cells Correlate with the Presence Of Published OnlineFirst March 27, 2020; DOI: 10.1158/1078-0432.CCR-19-1714 CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY Marrow-Infiltrating Regulatory T Cells Correlate with the Presence of Dysfunctional CD4þPD-1þ Cells and Inferior Survival in Patients with Newly Diagnosed Multiple Myeloma Nouf Alrasheed1, Lydia Lee1, Ehsan Ghorani1,2, Jake Y. Henry1,2, Lucia Conde3, Melody Chin1, Daria Galas-Filipowicz1, Andrew J.S. Furness1,2, Selina J. Chavda1, Huw Richards1, Dunnya De-Silva1, Oliver C. Cohen4, Dominic Patel5, Anthony Brooks6, Manuel Rodriguez-Justo5, Martin Pule1, Javier Herrero3, Sergio A. Quezada1,2, and Kwee L. Yong1 ABSTRACT ◥ Purpose: Immune dysregulation is described in multiple mye- (increased PD-1, LAG-3) compared with patients with lower fre- loma. While preclinical models suggest a role for altered T-cell quencies of Tregs. Analysis of CD4 and CD8 effectors revealed that immunity in disease progression, the contribution of immune low CD4effector (CD4eff):Treg ratio and increased frequency of PD- dysfunction to clinical outcomes remains unclear. We aimed to 1–expressing CD4eff cells were independent predictors of early characterize marrow-infiltrating T cells in newly diagnosed patients relapse over and above conventional risk factors, such as genetic and explore associations with outcomes of first-line therapy. risk and depth of response. Ex vivo functional analysis and RNA Experimental Design: We undertook detailed characterization sequencing revealed that CD4 and CD8 cells from patients with þ of T cells from bone marrow (BM) samples, focusing on immune greater abundance of CD4effPD-1 cells displayed transcriptional checkpoints and features of immune dysfunction, correlating with and secretory features of dysfunction. clinical features and progression-free survival. Conclusions: BM-infiltrating T-cell subsets, specifically Tregs Results: We found that patients with multiple myeloma had and PD-1–expressing CD4 effectors, negatively influence clinical greater abundance of BM regulatory T cells (Tregs) which, in turn, outcomes in newly diagnosed patients. Pending confirmation in expressed higher levels of the activation marker CD25 compared larger cohorts and further mechanistic work, these immune para- with healthy donors. Patients with higher frequencies of Tregs had meters may inform new risk models, and present potential targets shorter PFS and a distinct Treg immune checkpoint profile for immunotherapeutic strategies. Introduction evolution, host factors, including immunological fitness and function, likely also influence clinical outcomes of treatment. Multiple myeloma is a common cancer of plasma cells (PC) which is Accumulating evidence points toward a global immune dysregula- responsible for 2% of cancer deaths (1). Despite significant progress tion in multiple myeloma including impaired antigen presentation (3) seen with the inclusion of proteasome inhibitors and immunomod- and impaired T-cell effector function (4) with accumulation of sup- ulatory drugs (IMiD) into the mainstay of treatment regimens (2), pressive cell types (5, 6). These mechanisms appear to converge on myeloma remains almost universally incurable. Along with intrinsic disabling T cell–driven antitumor immunity (7) and accordingly drug sensitivities of tumor cells, and genomic drivers of clonal alterations in T-cell phenotype and function have been consistently reported in models of multiple myeloma. First, T regulatory cells 1Research Department of Haematology, University College London Cancer (Treg) suppress T-cell cytotoxicity and have been reported to be an Institute, London, United Kingdom. 2Cancer Immunology Unit, Research Depart- important driver of disease progression (8). Second, there appears to be ment of Haematology, University College London Cancer Institute, London, a relative reduction in cytotoxic T cells relative to Tregs (8). Third, United Kingdom. 3Bill Lyons Informatics Centre, University College London checkpoint proteins, such as the coinhibitory receptor, PD-1, are 4 Cancer Institute, London, United Kingdom. University College London Hospitals reported to be expressed on T cells from patients with multiple NHS Foundation Trust, London, United Kingdom. 5Department of Histopathol- 6 myeloma (9, 10) with increased expression of its ligand PD-L1 on ogy, University College London, London, United Kingdom. Institute of Child fl Health, University College London, London, United Kingdom. tumor cells (11). Despite these reports, the in uence of these altera- tions to T-cell phenotype on patient outcomes remains to be clarified. Note: Supplementary data for this article are available at Clinical Cancer Data regarding Treg numbers and relationship to clinical outcomes are Research Online (http://clincancerres.aacrjournals.org/). conflicting (12–14) and reports of increased PD-1 on T cells from L. Lee and E. Ghorani contributed equally to this article. S.A. Quezada and K.L. patients with multiple myeloma have not been generally corroborated Yong contributed equally to this article. or correlated to outcome (15). Reasons for these discrepancies include Corresponding Authors: Sergio A. Quezada and Kwee L. Yong, UCL Cancer different assay systems, examination of peripheral blood (PB) versus Institute, 72 Huntley Street, London WC1E 6BT, United Kingdom. Phone: 4420- marrow or the use of heterogenous patient cohorts. Many studies 7679-6139; Fax: 4420-7679-6222; E-mail: [email protected] and [email protected] included relapsed refractory patients, where the host immune system is likely to be affected by prior therapies, repeated infection, and Clin Cancer Res 2020;XX:XX–XX advanced disease. doi: 10.1158/1078-0432.CCR-19-1714 To resolve some of these issues, we investigated the marrow- Ó2020 American Association for Cancer Research. infiltrating T-cell populations in untreated patients with multiple AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 27, 2020; DOI: 10.1158/1078-0432.CCR-19-1714 Alrasheed et al. tomycin (Gibco; complete medium), at 37C with soluble anti-CD3 Translational Relevance (OKT3) and anti-CD28 (0.5 mg/mL, 15E8; Miltenyi Biotec). GolgiPlug Multiple myeloma is the second most common hematologic (1 mL/mL, BD Biosciences) was added for last 4 hours of incubation. malignancy and remains incurable. Beyond tumor biology and Cells were then stained for surface markers, CD4, CD8, CD69, and genomic features driving disease resistance, host factors includ- fixable viability dye, washed and fixed/permeabilized for staining for ing impaired immunity and frailty also contribute to poor intracellular TNFa, IFNg, IL2, and FoxP3 (Supplementary Table S2). outcomes. Despite reports of immune dysfunction in this cancer, clear evidence for the contribution to clinical outcomes remains RNA sequencing and analysis þ þ þ þ lacking. We show, for the first time, that high abundance of Treg RNA was extracted from flow sorted CD3 CD4 and CD3 CD8 þ and PD-1 CD4 effector cells in bone marrow of newly diag- cells from BM MNCs using ReliaPrep RNA Cell Miniprep System nosed patients are independent predictors of early relapse. This (Promega). cDNA libraries were prepared using the SMART-Seq v4 work supports growing literature on the importance of CD4 Ultra Low Input RNA Kit (Clontech Laboratories, Inc.). Samples were effector cells in multiple myeloma, and confirms a role for the sequenced on two lanes of the HiSeq 3000 instrument (Illumina) using PD-1/PD-L1 axis to multiple myeloma pathobiology. Our work a 75 bp paired-end run at UCL Institute of Child Health (London, UK). þ identifies Tregs and PD-1 CD4 effectors as potential therapeu- RNAseq data were processed with a modified version of the next- tic targets, and opens up avenues for further mechanistic studies flow nf-core RNAseq pipeline (https://github.com/nf-core/rnaseq). into early relapse. Pending confirmationinfuturepatient Reads were trimmed with TrimGalore v0.4.1, aligned against hg19 cohorts, such immune parameters may refine existing risk with STAR v2.5.2a, and duplicated reads were marked with Picard models, facilitating patient stratification for therapeutic strate- v2.18.9. Read counts per gene were generated with featureCounts gies targeting key CD4 populations. v1.6.2 and used for differential gene expression analysis. Gene set enrichment analysis (GSEA) was run using Gene Ontology pathways and previously reported sets of genes differentially expressed by dysfunctional CD4 (16–18) and CD8 T cells (19, 20). Human ortho- myeloma, with focus on Tregs and coinhibitory receptors seeking to logues of mouse genes were identified using Ensembl and NCBI understand the influence of these recognized suppressive T-cell popu- HomoloGene databases. lations on the clinical outcomes of first-line treatment. Statistical analysis Progression-free survival (PFS) was defined as time from start of Materials and Methods first-line therapy to first progression or death [as per International Patients and controls Myeloma Working Group criteria (21)]. Flow cytometric data were Bone marrow (BM) aspirates were obtained from patients with analyzed with FlowJo version 10 (Tree Star Inc). The percentage newly diagnosed (ND) multiple myeloma with written informed of a cell population expressing any given marker is designated as consent (Research ethics committee reference: 07/Q0502/17). Control “frequency” (of that marker) within the relevant Treg, CD4 effector, or BM aspirates (n
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