Immune Checkpoints OX40 and OX40L in Small-Cell Lung Cancer: Predict Prognosis and Modulate Immune Microenvironment

Chen, Peixin; Wang, Hao; Zhao, Lishu; Guo, Haoyue; Zhang, Liping; Zhang, Wei; Sun, Chengtao; Zhao, Sha; Li, Wei; Zhu, Jun; Yu, Jia; Wu, Chunyan; He, Yayi

doi:10.3389/fonc.2021.713853

Cited by 9 publications

(5 citation statements)

References 56 publications

(96 reference statements)

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“…[ 68 ] Studies in SCLC, melanoma, and pancreatic ductal adenocarcinoma have yielded similar results. [ 69 , 70 ] Our study did not show any significant survival benefit concerning OX40L expression, which might partly be explained by the low number of included cases. However, we found that AC TCs typically expressed OX40L at lower levels than other LNEN TCs.…”

Section: Discussioncontrasting

confidence: 57%

Expression patterns of novel immunotherapy targets in intermediate- and high-grade lung neuroendocrine neoplasms

Ferencz,

Török,

Pipek

et al. 2024

Cancer Immunol Immunother

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Background Advancements in immunotherapeutic approaches only had a modest impact on the therapy of lung neuroendocrine neoplasms (LNENs). Our multicenter study aimed to investigate the expression patterns of novel immunotherapy targets in intermediate- and high-grade LNENs. Methods The expressions of V-domain Ig suppressor of T cell activation (VISTA), OX40L, Glucocorticoid-induced TNF receptor (GITR), and T cell immunoglobulin and mucin domain 3 (TIM3) proteins were measured by immunohistochemistry in surgically resected tumor samples of 26 atypical carcinoid (AC), 49 large cell neuroendocrine lung cancer (LCNEC), and 66 small cell lung cancer (SCLC) patients. Tumor and immune cells were separately scored. Results Tumor cell TIM3 expression was the highest in ACs (p < 0.001), whereas elevated tumor cell GITR levels were characteristic for both ACs and SCLCs (p < 0.001 and p = 0.011, respectively). OX40L expression of tumor cells was considerably lower in ACs (vs. SCLCs; p < 0.001). Tumor cell VISTA expression was consistently low in LNENs, with no significant differences across histological subtypes. ACs were the least immunogenic tumors concerning immune cell abundance (p < 0.001). Immune cell VISTA and GITR expressions were also significantly lower in these intermediate-grade malignancies than in SCLCs or in LCNECs. Immune cell TIM3 and GITR expressions were associated with borderline prognostic significance in our multivariate model (p = 0.057 and p = 0.071, respectively). Conclusions LNEN subtypes have characteristic and widely divergent VISTA, OX40L, GITR, and TIM3 protein expressions. By shedding light on the different expression patterns of these immunotherapy targets, the current multicenter study provides support for the future implementation of novel immunotherapeutic approaches.

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Section: Discussioncontrasting

confidence: 57%

Expression patterns of novel immunotherapy targets in intermediate- and high-grade lung neuroendocrine neoplasms

Ferencz,

Török,

Pipek

et al. 2024

Cancer Immunol Immunother

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“… 207 Mouse models have shown that specific antibodies that stimulate OX40 can reduce the number of Tregs, thereby maintaining the function of effector T cells and showing high antitumor activity. 208 – 210 …”

Section: Immune Stimulatory Molecules On T Cellsmentioning

confidence: 99%

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Wang

Sun

2022

Sig Transduct Target Ther

172

114

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Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatments. Among them, immune checkpoint blocking therapy, represented by PD-1/PD-L1 inhibitors (nivolumab) and CTLA-4 inhibitors (ipilimumab), has shown encouraging therapeutic effects in the treatment of various malignant tumors, such as non-small cell lung cancer (NSCLC) and melanoma. In addition, with the advent of CAR-T, CAR-M and other novel immunotherapy methods, immunotherapy has entered a new era. At present, evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect. However, the overall clinical response rate of tumor immunotherapy still needs improvement, which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents. Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future. In this article, we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.

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“…The absence of functional and cell type-specific methylation analyses in our study does not allow us to conclude causal methylation repatterning of immune checkpoint genes due to BAP1 aberrancy in uveal melanoma. However, there is emerging evidence pointing towards an expression of immune cell-specific immune checkpoint genes, for example, GITR, OX40, 4-1BB, CD27, and CD40, in tumor cells [24][25][26][27][28]. Yan et al could prove that melanoma cell-intrinsic CD40 plays an important role in the inhibition of tumor growth and is able to induce malignant cell death [29].…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of GITR, OX40, 4-1BB, CD27, and CD40 correlates with BAP1 aberrancy and prognosis in uveal melanoma

Hoffmann¹,

Fröhlich²,

Sirokay³

et al. 2023

Melanoma Research

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Uveal melanoma represents an aggressive tumor that responds mostly poorly to established melanoma treatments. Comprehensive methylation profiling of the next-generation immunotherapeutic target genes, for example, members of the tumor necrosis factor receptor superfamily, might allow for the development of companion predictive biomarkers. We have analyzed CpG sites within the immune checkpoint genes GITR, OX40, 4-1BB, CD27, and CD40 probed by the Illumina Infinium HumanMethylation450 BeadChip in N = 80 uveal melanomas included in The Cancer Genome Atlas with regard to BAP1 aberrancy, mRNA expression, and overall survival. In all analyzed immune checkpoint genes, BAP1 aberrancy was associated with decreased CpG methylation levels. We identified specific CpG sites that significantly correlated with BAP1 aberrancy, mRNA expression levels, and overall survival. Our results suggest epigenetic regulation of the analyzed immune checkpoint genes via DNA methylation in uveal melanoma and provide rationale for methylation testing in biomarker programs in clinical trials.

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Immune Checkpoints OX40 and OX40L in Small-Cell Lung Cancer: Predict Prognosis and Modulate Immune Microenvironment

Cited by 9 publications

References 56 publications

Expression patterns of novel immunotherapy targets in intermediate- and high-grade lung neuroendocrine neoplasms

Expression patterns of novel immunotherapy targets in intermediate- and high-grade lung neuroendocrine neoplasms

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

DNA methylation of GITR, OX40, 4-1BB, CD27, and CD40 correlates with BAP1 aberrancy and prognosis in uveal melanoma

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