Ryan T. Sowell
Rush University Medical Center
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Publication
Featured researches published by Ryan T. Sowell.
Cell | 2017
Michael D. Buck; Ryan T. Sowell; Susan M. Kaech; Erika L. Pearce
Choices have consequences. Immune cells survey and migrate throughout the body and sometimes take residence in niche environments with distinct communities of cells, extracellular matrix, and nutrients that may differ from those in which they matured. Imbedded in immune cell physiology are metabolic pathways and metabolites that not only provide energy and substrates for growth and survival, but also instruct effector functions, differentiation, and gene expression. This review of immunometabolism will reference the most recent literature to cover the choices that environments impose on the metabolism and function of immune cells and highlight their consequences during homeostasis and disease.
Blood | 2009
Atef Allam; Dietrich B. Conze; Maria Letizia Giardino Torchia; Ivana Munitic; Hideo Yagita; Ryan T. Sowell; Amanda L. Marzo; Jonathan D. Ashwell
The ability of the adaptive immune system to respond rapidly and robustly upon repeated antigen exposure is known as immunologic memory, and it is thought that acquisition of memory T-cell function is an irreversible differentiation event. In this study, we report that many phenotypic and functional characteristics of antigen-specific CD8 memory T cells are lost when they are deprived of contact with dendritic cells. Under these circumstances, memory T cells reverted from G(1) to the G(0) cell-cycle state and responded to stimulation like naive T cells, as assessed by proliferation, dependence upon costimulation, and interferon-gamma production, without losing cell surface markers associated with memory. The memory state was maintained by signaling via members of the tumor necrosis factor receptor superfamily, CD27 and 4-1BB. Foxo1, a transcription factor involved in T-cell quiescence, was reduced in memory cells, and stimulation of naive CD8 cells via CD27 caused Foxo1 to be phosphorylated and emigrate from the nucleus in a phosphatidylinositol-3 kinase-dependent manner. Consistent with these results, maintenance of G(1) in vivo was compromised in antigen-specific memory T cells in vesicular stomatitis virus-infected CD27-deficient mice. Therefore, sustaining the functional phenotype of T memory cells requires active signaling and maintenance.
Journal of Immunology | 2014
Ryan T. Sowell; Magdalena Rogozinska; Christine E. Nelson; Vaiva Vezys; Amanda L. Marzo
Mucosal tissues are subject to frequent pathogen exposure and are major sites for transmission of infectious disease. CD8 T cells play a critical role in controlling mucosa-acquired infections even though their migration into mucosal tissues is tightly regulated. The mechanisms and signals that control the formation of tissue-resident memory CD8 T cells are poorly understood; however, one key regulator of memory CD8 T cell differentiation, mammalian target of rapamycin kinase, can be inhibited by rapamycin. We report that, despite enhancing the formation of memory CD8 T cells in secondary lymphoid tissues, rapamycin inhibits the formation of resident memory CD8 T cells in the intestinal and vaginal mucosa. The ability of rapamycin to block the formation of functional resident CD8 T cells in mucosal tissues protected mice from a model of CD8 T cell–mediated lethal intestinal autoimmunity. These findings demonstrate an opposing role for mammalian target of rapamycin in the formation of resident versus nonresident CD8 T cell immunity.
Cancer Discovery | 2017
Scott N. Gettinger; Jungmin Choi; Katherine Hastings; Anna Truini; Ila Datar; Ryan T. Sowell; Anna Wurtz; Weilai Dong; Guoping Cai; Mary Ann Melnick; Victor Y. Du; Joseph Schlessinger; Sarah B. Goldberg; Anne C. Chiang; Miguel F. Sanmamed; Ignacio Melero; Jackeline Agorreta; Luis M. Montuenga; Richard P. Lifton; Soldano Ferrone; Paula B. Kavathas; David L. Rimm; Susan M. Kaech; Kurt A. Schalper; Roy S. Herbst; Katerina Politi
Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.Significance: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer. Cancer Discov; 7(12); 1420-35. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.
Journal of Immunological Methods | 2014
Mariana M. Mata; Fareeha Mahmood; Ryan T. Sowell; Linda L. Baum
Freshly isolated PBMC are broadly used as effector cells in functional assays that evaluate antibody-dependent cell mediated cytotoxicity (ADCC) and NK activity; however, they introduce natural-individual donor-to-donor variability. Cryopreserved PBMC provide a more consistent source of effectors than fresh cells in cytotoxicity assays. Our objective was to determine the effects of cryopreservation of effector PBMC on cell frequency, and on the magnitude and specificity of ADCC and NK activity. Fresh, frozen/overnight rested and frozen/not rested PBMC were used as effector cells in (51)Cr-release and CD107a degranulation assays. Frozen/overnight rested PBMC had higher ADCC and NK activity in both assays when compared to fresh PBMC; however, when using frozen/not rested PBMC, ADCC and NK activities were significantly lower than fresh PBMC. Background CD107a degranulation in the absence of target cell stimulation was greater in PBMC that were frozen/not rested when compared to fresh PBMC or PBMC that were frozen overnight and rested. The percentages of CD16(+)CD56(dim) NK cells and CD14(+) monocytes were lower in PBMC that were frozen and rested overnight than in fresh PBMC. CD16 expression on CD56(dim) NK cells was similar for all PBMC treatments. PBMC that were frozen and rested overnight were comparable to fresh PBMC effectors. PBMC that were frozen and used immediately when evaluating ADCC or NK activity using either a (51)Cr-release assay or a CD107a degranulation assay had the lowest activity. Clinical studies of antibodies that mediate ADCC would benefit from using effector cells that have been frozen, thawed and rested overnight prior to assay.
Journal of Immunology | 2017
Ryan T. Sowell; Josef W. Goldufsky; Magdalena Rogozinska; Zurisaday Quiles; Yanxia Cao; Eliseo F. Castillo; Alison Finnegan; Amanda L. Marzo
IL-15 is an essential cytokine known to promote T cell survival and activate the effector function of memory phenotype CD8 T cells. Blocking IL-15 signals also significantly impacts tissue-specific effector and memory CD8 T cell formation. In this study, we demonstrate that IL-15 influences the generation of memory CD8 T cells by first promoting their accumulation into mucosal tissues and second by sustaining expression of Bcl-6 and T-bet. We show that the mechanism for this recruitment is largely dependent on mammalian target of rapamycin and its subsequent inactivation of FoxO1. Last, we show that IL-15 complexes delivered locally to mucosal tissues without reinfection is an effective strategy to enhance establishment of tissue resident memory CD8 T cells within mucosal tissues. This study provides mechanistic insight into how IL-15 controls the generation of memory CD8 T cells and influences their trafficking and ability to take up residence within peripheral tissues.
Frontiers in Immunology | 2015
Ryan T. Sowell; Amanda L. Marzo
Tissues such as the lung, skin, intestinal epithelium, and reproductive tract serve as a barricade against pathogen exposure for the entire body. Specifically within the skin and mucosal tissues, a population of resident CD8 T cells plays a salient role in the protection against infection. Resident-memory CD8 T cells (TRM) are a long-lived subset of memory CD8 T cells that do not re-circulate after taking up residence in the tissues. Traditionally memory CD8 T cells were conceptually divided into two subsets central (TCM) and effector (TEM) memory where TCM preferentially localized within secondary lymphoid tissues (SLO) and TEM circulated throughout the peripheral tissues. While the concept of TCM and TEM has been considerably explored, memory CD8 T cells found within barrier tissues do not totally fit within the TCM/TEM paradigm. Through the study of circulating CD8 T cells, our understanding of memory CD8 T cells has grown tremendously in the last 25 years. We now understand that it is not sufficient to simply generate large numbers of circulating memory CD8 T cells in order to enhance protection against localized infection. Developing clinical strategies that can enhance protection against mucosal pathogens will require a clear understanding of how memory CD8 T cells are generated and maintained within barrier tissues at the sites of initial pathogen exposure. We will outline our current understanding of TRM in respect to their generation, functional importance, and how future studies must shed light on how we can exploit TRM to develop the next generation of effective vaccines.
Advances in Experimental Medicine and Biology | 2010
Amanda L. Marzo; Ryan T. Sowell; Bernadette Scott
Immunological memory is considered the hallmark of adaptive, or acquired, immunity. That ability of our immune system to recognize and respond to those pathogens we have encountered before not only typifies acquired immunity but has provided the basis for the most notable of medical interventions: vaccination. Yet, as much as we now know about this process, we are still on the cusp of fully understanding how memory T cells develop, how they are maintained and the importance of memory T-cell heterogeneity. In this review we will primarily focus on our understanding of CD8 T-cell memory generated during acute infections and how precursor frequency influences their development and functional attributes.
Nature Communications | 2018
Scott N. Gettinger; Jungmin Choi; Nikita Mani; Miguel F. Sanmamed; Ila Datar; Ryan T. Sowell; Victor Y. Du; Edward Kaftan; Sarah B. Goldberg; Weilai Dong; Daniel Zelterman; Katerina Politi; Paula B. Kavathas; Susan M. Kaech; Xiaoqing Yu; Hongyu Zhao; Joseph Schlessinger; Richard P. Lifton; David L. Rimm; Lieping Chen; Roy S. Herbst; Kurt A. Schalper
The biological determinants of sensitivity and resistance to immune checkpoint blockers are not completely understood. To elucidate the role of intratumoral T-cells and their association with the tumor genomic landscape, we perform paired whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) in pre-treatment samples from non-small cell lung carcinoma (NSCLC) patients treated with PD-1 axis blockers. QIF is used to simultaneously measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3) and effector capacity (Granzyme-B in CD3). Elevated mutational load, candidate class-I neoantigens or intratumoral CD3 signal are significantly associated with favorable response to therapy. Additionally, a “dormant” TIL signature is associated with survival benefit in patients treated with immune checkpoint blockers characterized by elevated TILs with low activation and proliferation. We further demonstrate that dormant TILs can be reinvigorated upon PD-1 blockade in a patient-derived xenograft model.Immune checkpoint blockade (ICB) only induces tumour response in a subset of non-small cell lung carcinomas (NSCLC). Here the authors do whole genome sequencing and multiplexed quantitative immunofluorescence on patient samples and identify a “dormant” T-cell signature associated with sensitivity to ICB.
Cell Reports | 2016
Frederick J. Kohlhapp; Erica J. Huelsmann; Andrew T. Lacek; Jason M. Schenkel; Jevgenijs Lusciks; Joseph Broucek; Josef W. Goldufsky; Tasha Hughes; Janet P. Zayas; Hubert Dolubizno; Ryan T. Sowell; Regina Kühner; Sarah Burd; John C. Kubasiak; Arman Nabatiyan; Sh’Rae Marshall; Praveen K. Bommareddy; Shengguo Li; Jenna Newman; Claude E. Monken; Sasha H. Shafikhani; Amanda L. Marzo; José A. Guevara-Patiño; Ahmed Lasfar; Paul G. Thomas; Edmund C. Lattime; Howard L. Kaufman; Andrew Zloza