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

Fousek, Kristen; Horn, Lucas A.; Qin, Haiyan; Dahut, Madeline; Iida, Masafumi; Yacubovich, Dan; Hamilton, Duane H.; Thomas, Anish; Schlom, Jeffrey; Palena, Claudia

doi:10.1016/j.jtho.2022.11.008

Cited by 14 publications

(8 citation statements)

References 32 publications

(48 reference statements)

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“…(18) Activation of NK cells in SCLC by the interleukin-15 superagonist allows them to exhibit increased cytotoxicity and kill SCLC tumor cells across all variant molecular subtypes. (19) These studies all support our conclusion.…”

Section: Discussionsupporting

confidence: 82%

Identification of NK cell to predict prognosis in extensive-stage small cell lung cancer patients treated with immunotherapy plus chemotherapy

Cui

Zhao

et al. 2023

Preprint

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Background Although the combination of immunotherapy and chemotherapy has emerged as a new standard for the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC), there remains a dearth of prognostic markers of this novel therapeutic approach. In this study, we aimed to evaluate the efficacy of immunotherapy plus chemotherapy in patients with ES-SCLC and explore the potential prognostic markers. Methods Pathologically confirmed ES-SCLC patients receiving immunotherapy plus chemotherapy as the first-line treatment were enrolled between July 2020 and August 2022 in this retrospective study. The natural killer (NK) cells in peripheral blood was collected at sequential time points. Kaplan-Meier method and log-rank test were utilized to calculate progression-free survival (PFS) and overall survival (OS). The prognostic value of the percentage of NK cells was evaluated by Cox proportional hazards regression analyses. Results A total of 33 patients with ES-SCLC treated with immunotherapy plus platinum-etoposide were included for the analysis. At the time of data cutoff, the median PFS was 5.6 months and the median OS was 13.9 months. It was found that the percentage of NK cells at baseline was an independent factor of PFS(HR 0.142; 95% CI, 0.053–0.377; P＜0.001), and the difference between NK cell percentage at the time of optimal efficacy and baseline was an independent predictor factor of OS(HR 0.375; 95% CI, 0.169–0.832; P = 0.016). Conclusions The study demonstrated that NK cells in peripheral blood could be used as a novel and convenient biomarker to predict the prognosis of patients with ES-SCLC treated with immunotherapy plus chemotherapy,which has significant implications for informing treatment decisions.

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Section: Discussionsupporting

confidence: 82%

Identification of NK cell to predict prognosis in extensive-stage small cell lung cancer patients treated with immunotherapy plus chemotherapy

Cui

Zhao

et al. 2023

Preprint

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“…Moreover, previous studies have reported that IL15 superagonist-stimulated NK cells enhance in vivo antitumor efficacy by promoting tumor infiltration [30], and IL15-expanded KLRG1 + NK cells protect mice from pulmonary metastatic colorectal carcinoma [10]. It is increasingly clear that β-glucans can enhance antitumor effects by stimulating immune cells, although they lack direct cytotoxic effects on tumor cells [31].…”

Section: Discussionmentioning

confidence: 99%

In Vivo Zymosan Treatment Induces IL15-Secreting Macrophages and KLRG1-Expressing NK Cells in Mice

Park,

Lee,

Park

et al. 2023

Molecules

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Beta-glucan (β-glucan) is a natural polysaccharide produced by fungi, bacteria, and plants. Although it has been reported that β-glucan enhances innate immune memory responses, it is unclear whether different types of β-glucans display similar immune effects. To address this issue, we employed zymosan (β-1,3-glycosidic linkage) and pustulan (β-1,6-glycosidic linkage) to investigate their in vivo effects on innate memory immune responses. We examined the changes of innate memory-related markers in macrophages and natural killer (NK) cells, two immune cell types that display innate memory characteristics, at two different time points (16 h and 7 days) after β-glucan stimulation. We found that short-term (16 h) zymosan treatment significantly induced macrophages to upregulate IL15 production and increased surface IL15Rα expression on NK cells. In addition, long-term (7 days) zymosan treatment significantly induced macrophages to upregulate the expression of innate memory-related markers (e.g., TNFα, HIF1α, and mTOR) and induced NK cells to express enhanced levels of KLRG1, known as an innate memory-like marker. Our results provide support that zymosan can be an effective adjuvant to promote innate memory immune responses, providing a bridge between innate and adaptive immune cells to enhance various immune responses such as those directed against tumors.

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“…Given the broad use of the SCLC-Y cell lines we now identify to be SMARCA4-UT in therapeutic studies, our findings provide new insight into potential therapeutic vulnerabilities in SMARCA4-deficient malignancies. For example, the IL-15 super-agonist, N-808 ( 43 ), arginine deprivation ( 44 ), and inhibition of Aurora kinase B ( 45 ), checkpoint kinase 1 (CHK1; ref. 46 ) have all demonstrated anticancer activity in SMARCA4-deficient SCLC-Y cell lines.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Pathologic Characterization of YAP1-Expressing Small Cell Lung Cancer Cell Lines Leads to Reclassification as SMARCA4-Deficient Malignancies

Ng,

Cai,

Girard

et al. 2023

Clinical Cancer Research

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Purpose: The classification of small cell lung cancer (SCLC) into distinct molecular subtypes defined by ASCL1, NEUROD1, POU2F3, or YAP1 (SCLC-A, -N, -P, or -Y) expression, paves the way for a personalized treatment approach. However, the existence of a distinct YAP1-expressing SCLC subtype remains controversial. Experimental Design: To better understand YAP1-expressing SCLC, the mutational landscape of human SCLC cell lines was interrogated to identify pathogenic alterations unique to SCLC-Y. Xenograft tumors, generated from cell lines representing the four SCLC molecular subtypes, were evaluated by a panel of pathologists who routinely diagnose thoracic malignancies. Diagnoses were complemented by transcriptomic analysis of primary tumors and human cell line datasets. Protein expression profiles were validated in patient tumor tissue. Results: Unexpectedly, pathogenic mutations in SMARCA4 were identified in six of eight SCLC-Y cell lines and correlated with reduced SMARCA4 mRNA and protein expression. Pathologist evaluations revealed that SMARCA4-deficient SCLC-Y tumors exhibited features consistent with thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT). Similarly, the transcriptional profile SMARCA4-mutant SCLC-Y lines more closely resembled primary SMARCA4-UT, or SMARCA4-deficient non–small cell carcinoma, than SCLC. Furthermore, SMARCA4-UT patient samples were associated with a YAP1 transcriptional signature and exhibited strong YAP1 protein expression. Together, we found little evidence to support a diagnosis of SCLC for any of the YAP1-expressing cell lines originally used to define the SCLC-Y subtype. Conclusions: SMARCA4-mutant SCLC-Y cell lines exhibit characteristics consistent with SMARCA4-deficient malignancies rather than SCLC. Our findings suggest that, unlike ASCL1, NEUROD1, and POU2F3, YAP1 is not a subtype defining transcription factor in SCLC.

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

Cited by 14 publications

References 32 publications

Identification of NK cell to predict prognosis in extensive-stage small cell lung cancer patients treated with immunotherapy plus chemotherapy

Identification of NK cell to predict prognosis in extensive-stage small cell lung cancer patients treated with immunotherapy plus chemotherapy

In Vivo Zymosan Treatment Induces IL15-Secreting Macrophages and KLRG1-Expressing NK Cells in Mice

Molecular and Pathologic Characterization of YAP1-Expressing Small Cell Lung Cancer Cell Lines Leads to Reclassification as SMARCA4-Deficient Malignancies

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