Harnessing the IL-7/IL-7R<b>α</b>axis to improve tumor immunotherapy

Johnson, Christopher; Wrangle, John; Mehrotra, Shikhar; Li, Zihai; Paulos, Chrystal M.; Cole, David J.; Surh, Charles D.; Rubinstein, Mark P.

doi:10.1080/2162402x.2015.1122865

Cited by 4 publications

(3 citation statements)

References 11 publications

(18 reference statements)

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“…Furthermore, recent preclinical studies have shown that IL-7 treatment promotes CD4 T cell poly-functionality leading to tumor containment ( Ding et al, 2016 ). In combination with IL-12 pre-priming of antigen-experienced CD8 T cells, IL-7 can induce cellular proliferation after IL-12 withdrawal ( Johnson et al, 2016 ). Thus, both IL-2 and IL-7 have a direct influence on fine-tuning the repertoire of anti-cancer T-cells in the host.…”

Section: Discussionmentioning

confidence: 99%

Mesothelin-specific Immune Responses Predict Survival of Patients With Brain Metastasis

et al. 2017

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BackgroundPatients with advanced malignancies, e.g. lung cancer, ovarian cancer or melanoma, frequently present with brain metastases. Clinical presentation and disease progression of cancer is in part shaped by the interaction of the immune system with malignant cells. Antigen-targeted immune responses have been implicated in the prolonged survival of patients with cancer. This includes the tumor-associated antigen (TAA) mature mesothelin, a 40 kDa cell surface-bound antigen that is overexpressed in several malignancies including lung ovarian and pancreatic cancer. We examined in an observational, prospective study the survival of patients with brain metastases in association with clinical parameters and cellular immune responses to molecularly defined TAAs or viral (control) target antigens.MethodsImmune cells in peripheral blood obtained from thirty-six patients with brain metastases were tested for cytokine production in response to a broad panel of defined viral and TAA target antigens, including full-length mesothelin. Incubation of immune cells with antigenic targets was carried out in i) medium alone, (ii) in a cytokine cocktail of interleukin (IL)-2/IL-15/IL-21, or (iii) IL-2/IL-7. Supernatants were tested for interferon gamma (IFN-γ) production, after which univariate and multivariate analyses (Cox stepwise regression model) were performed to identify independent clinical and immunological factors associated with patient survival. Patients were followed-up for at least 500 days after surgery or until death.FindingsUnivariate analysis identified age, gender, radiotherapy and mutational load as clinical parameters affecting survival of patients with brain metastases. Cox multivariate analysis showed that radiotherapy (P = 0·004), age (P = 0·029) and IFN-γ responses to mature mesothelin, conditioned by IL-2/IL-7 (P = 0·045) were independent predictors of the survival of patients from surgery up to follow-up or death.InterpretationThis is the first evidence that immune responses to mesothelin serve as a marker of increased overall survival in patients with brain metastases, regardless of the primary tumor origin. Analyses of immunological markers could potentially serve as prognostic markers in patients with brain metastases and help to select patients in need for adjunct, immunological, treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Mesothelin-specific Immune Responses Predict Survival of Patients With Brain Metastasis

et al. 2017

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“…It enhances the retroviral transduction efficiency of TCRs while preserving the effector function and expansion potential of the transduced T cells [ 177 ]. CD8 + T cells activated with exogenous IL-12 have elevated IL-7 receptor expression and rely on IL-7 for persistence and antitumor immunity [ 178 ]. The pre-treatment of T cells with IL-12 in vitro enhances the release of a range of cytokines (including IFNγ, TNFα, IL-13, IL-4, and IL-10), potentially by altering certain TCR signaling pathways (including increased pAkt, p-p38, and p-Lck signaling) and by enhancing oxidative metabolism [ 179 ].…”

Section: Cytokine Signaling In Dictating T Cell Metabolismmentioning

confidence: 99%

New Developments in T Cell Immunometabolism and Implications for Cancer Immunotherapy

Oberholtzer

Quinn

Chakraborty

et al. 2022

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Despite rapid advances in the field of immunotherapy, the elimination of established tumors has not been achieved. Many promising new treatments such as adoptive cell therapy (ACT) fall short, primarily due to the loss of T cell effector function or the failure of long-term T cell persistence. With the availability of new tools and advancements in technology, our understanding of metabolic processes has increased enormously in the last decade. Redundancy in metabolic pathways and overlapping targets that could address the plasticity and heterogenous phenotypes of various T cell subsets have illuminated the need for understanding immunometabolism in the context of multiple disease states, including cancer immunology. Herein, we discuss the developing field of T cell immunometabolism and its crucial relevance to improving immunotherapeutic approaches. This in-depth review details the metabolic pathways and preferences of the antitumor immune system and the state of various metabolism-targeting therapeutic approaches.

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“…The cytokines with the common γ chain (γc-CD132) family such as IL-2, IL-7, IL-15 and IL-21, significantly, induce Tscm differentiation, and the downstream of cytokines signaling involves JAK1/3, STAT3/5, followed by the PI3K/AKT/mTOR and Ras/Raf/MAPK-ERK cascades and the consequently increased activation of c-fos/jun, c-Myc, NF-κB and Bcl-2 and the decreased expression of PUMA and Bim promote CD8+ T-cell proliferation and survival [8]. These cytokines effectively drive CD8+ T cells into stem-like phenotypes in vitro and vivo, with different methods [9,10]: the addition of soluble recombinant cytokines to the culture medium of CART in vitro; the systemic administration of recombinant cytokines into the patient with adoptive CD8+ T-cell therapy (ACT); the increase of cytokine receptors of CD8+ T cells: IL-7 receptor transduction contributes GD2-CAR-T the long-term and superior elimination to neuroblastoma cells, and antiapoptosis function of upregulation of bcl-2 [11]; the heterodimer cytokine and its receptor on CD8+ T cells. IL-15/IL-15Rα IgG1-Fc heterodimer: IL-15 (IL-15N72D) binding to IL-15 receptor α chain and IgG Fc fusion, is almost 25-fold effective than rhIL-15, even promotes T-cell function without lymphodepletion [12]; and IL-2-JAK-STAT3/5 pathway: a new CD19-CAR-T construct a truncated cytoplasmic domain from the IL-2 receptor β-chain (IL-2Rβ) and a STAT3binding tyrosine-X-X-glutamine (YXXQ) motif, together with the TCR signaling and CD28 domains, which owns the superior proliferative and antitumor ability via antigen-dependent activation of JAK-STAT3/5, with the CD45RA + CD62L + CCR7 + phenotype [13].…”

Section: Signaling 3 Pathway and Tscm Generationmentioning

confidence: 99%