Dataset Information

An Interleukin-15 Superagonist Enables Antitumor Efficacy of Natural Killer Cells Against All Molecular Variants of SCLC.

ABSTRACT:

Introduction

SCLC is a highly aggressive tumor with a 5-year survival rate of less than 6%. A heterogeneous disease, SCLC is classified into four subtypes that include tumors with neuroendocrine and non-neuroendocrine features. Immune checkpoint blockade has been recently added for the frontline treatment of SCLC; however, this therapy has only led to modest clinical improvements. The lack of clinical benefit in a cancer type known to have a high tumor mutational burden has been attributed to poor T-cell infiltration and low expression of MHC-class I in most SCLC tumors. In an attempt to devise a more effective immunotherapeutic regimen, this study investigated an alternate approach on the basis of the use of the clinical-stage interleukin-15 superagonist, N-803.

Methods

Preclinical models of SCLC spanning all molecular subtypes were used to evaluate the susceptibility of SCLC to natural killer (NK)-mediated lysis in vitro, including NK cells activated by N-803. Antitumor activity of N-803 was evaluated in vivo with a xenograft model of SCLC.

Results

In vitro and in vivo data revealed differences in susceptibility of SCLC subtypes to lysis by NK cells and that NK cells activated by N-803 effectively lyse SCLC tumor cells across all variant subtypes, regardless of their expression of MHC-class I.

Conclusions

These findings highlight the potential of a novel immune-based intervention using a cytokine-based therapeutic option for the treatment of SCLC. We hypothesize that N-803 may provide benefit to most patients with SCLC, including those with immunologically cold tumors lacking MHC expression.

SUBMITTER: Fousek K

PROVIDER: S-EPMC9974560 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

An Interleukin-15 Superagonist Enables Antitumor Efficacy of Natural Killer Cells Against All Molecular Variants of SCLC.

Fousek Kristen K Horn Lucas A LA Qin Haiyan H Dahut Madeline M Iida Masafumi M Yacubovich Dan D Hamilton Duane H DH Thomas Anish A Schlom Jeffrey J Palena Claudia C

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20221121 3

<h4>Introduction</h4>SCLC is a highly aggressive tumor with a 5-year survival rate of less than 6%. A heterogeneous disease, SCLC is classified into four subtypes that include tumors with neuroendocrine and non-neuroendocrine features. Immune checkpoint blockade has been recently added for the frontline treatment of SCLC; however, this therapy has only led to modest clinical improvements. The lack of clinical benefit in a cancer type known to have a high tumor mutational burden has been attribut ...[more]

PMID: 36410696

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Project description:Natural killer (NK) cells belong to the first line of host defense against infection and cancer. Cytokines, including interleukin-15 (IL-15), critically regulate NK cell activity, resulting in recognition and direct killing of transformed and infected target cells. NK cells have to adapt and respond in inflamed and often hypoxic areas. Cellular stabilization and accumulation of the transcription factor hypoxia-inducible factor-1α (HIF-1α) is a key mechanism of the cellular hypoxia response. At the same time, HIF-1α plays a critical role in both innate and adaptive immunity. While the HIF-1α hydroxylation and degradation pathway has been recently described with the help of mathematical methods, less is known concerning the mechanistic mathematical description of processes regulating the levels of HIF-1α mRNA and protein. In this work we combine mathematical modeling with experimental laboratory analysis and examine the dynamic relationship between HIF-1α mRNA, HIF-1α protein, and IL-15-mediated upstream signaling events in NK cells from human blood. We propose a system of non-linear ordinary differential equations with positive and negative feedback loops for describing the complex interplay of HIF-1α regulators. The experimental design is optimized with the help of mathematical methods, and numerical optimization techniques yield reliable parameter estimates. The mathematical model allows for the investigation and prediction of HIF-1α stabilization under different inflammatory conditions and provides a better understanding of mechanisms mediating cellular enrichment of HIF-1α. Thanks to the combination of in vitro experimental data and in silico predictions we identified the mammalian target of rapamycin (mTOR), the nuclear factor-κB (NF-κB), and the signal transducer and activator of transcription 3 (STAT3) as central regulators of HIF-1α accumulation. We hypothesize that the regulatory pathway proposed here for NK cells can be extended to other types of immune cells. Understanding the molecular mechanisms involved in the dynamic regulation of the HIF-1α pathway in immune cells is of central importance to the immune cell function and could be a promising strategy in the design of treatments for human inflammatory diseases and cancer.

Dataset Information

An Interleukin-15 Superagonist Enables Antitumor Efficacy of Natural Killer Cells Against All Molecular Variants of SCLC.

Introduction

Methods

Results

Conclusions

Publications

An Interleukin-15 Superagonist Enables Antitumor Efficacy of Natural Killer Cells Against All Molecular Variants of SCLC.

Similar Datasets

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