Impact of immune checkpoint gene CD155 Ala67Thr and CD226 Gly307Ser polymorphisms on small cell lung cancer clinical outcome

Lee, Jang Hyuck; Yoo, Seung Soo; Hong, Mi Jeong; Choi, Jin Eun; Kim, Soyoun; Kang, Hyunwoo; Do, Sook Kyung; Kim, Ji Hyun; Baek, Sun Ah; Lee, Won Kee; Yoo, Jae Do; Choi, Sun Ha; Lee, Yong Hoon; Seo, Hyewon; Lee, Jaehee; Lee, Shin Yup; Ick, Seung; Kim, Chang Ho; Park, Jae Yong

doi:10.1038/s41598-021-81260-1

Cited by 3 publications

(6 citation statements)

References 45 publications

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“…Consistently, mutant CD155 generated a stronger DNAM‐1 signal than did WT CD155 in a reporter cell assay (Figure S2A). Thus, our results were inconsistent with the previous report 8 . A possible explanation for the differences from the previous study is a difference in organisms of DNAM‐1.…”

Section: Resultscontrasting

confidence: 99%

“…Thus, our results were inconsistent with the previous report. 8 A possible explanation for the differences from the previous study is a difference in organisms of DNAM-1. In the present study, we used human CD155 and human DNAM-1, while the previous study used human CD155 and mouse DNAM-1 as a template for computational 3D structural analysis.…”

Section: The Mutation (Ala67thr) Increased the Binding Affinity Of Cd...contrasting

confidence: 62%

“…Interestingly, a single‐nucleotide polymorphism rs1058402G>A (Ala67Thr) causes a mutation to Thr from Ala at residue 67 of CD155 (Figure S1). A recent study showed that the mutation is associated with worse overall survival of patients with small cell lung cancer and suggested that this is caused by the decreased binding affinity of mutant CD155 for DNAM‐1 as a result of the 3D structural analysis 8 . However, we unexpectedly found that the mutation increased the binding affinity of mutant CD155 for TIGIT rather than decreased the binding affinity for DNAM‐1 and induced a stronger TIGIT signal in reporter cells and NK cells than WT CD155.…”

Section: Introductionmentioning

confidence: 99%

“…A recent study showed that the mutation is associated with worse overall survival of patients with small cell lung cancer and suggested that this is caused by the decreased binding affinity of mutant CD155 for DNAM-1 as a result of the 3D structural analysis. 8…”

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CD155 mutation (Ala67Thr) increases the binding affinity for and the signaling via an inhibitory immunoreceptor TIGIT

et al. 2022

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CD155 is a shared ligand for activating and inhibitory immunoreceptors DNAX accessory molecule 1 (DNAM‐1), also called CD226, and T cell immunoglobulin and immunoreceptor tyrosine‐based inhibitory motif domain (TIGIT), which are expressed on natural killer (NK) cells and T cells, and positively and negatively regulates tumor immune responses, respectively. A recent study showed that the single nucleotide polymorphism rs1058402G>A causing a mutation to Thr from Ala at residue 67 of CD155 is associated with worse overall survival of patients with small cell lung cancer and suggested that this is caused by the decreased affinity of mutant CD155 for DNAM‐1 as a result of the 3D structural analysis. Unexpectedly, however, we found that the mutation increased the binding affinity for TIGIT rather than decreased the binding affinity for DNAM‐1 and induced a stronger signal than WT CD155. Our results suggest that the mutation suppresses tumor immune responses by generating a stronger inhibitory signal in immune cells in the tumor microenvironment.

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Section: Resultscontrasting

confidence: 99%

Section: The Mutation (Ala67thr) Increased the Binding Affinity Of Cd...contrasting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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CD155 mutation (Ala67Thr) increases the binding affinity for and the signaling via an inhibitory immunoreceptor TIGIT

et al. 2022

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“…Antibodies that inhibit the interaction of PD1/PDL1 have been authorized for the treatment of a variety of cancers, including metastatic bladder cancer. Due to the fact that the PD1/PDL1 pathway suppresses immune cell responses, inhibiting the PD-1/PD-L1 pathway enables immune cells to attack tumors [ 29 ]. However, only a small number (20%) of MIBC patients are responsive to immunotherapy [ 5 ], which limits the clinical use and makes it important to select the potential responders.…”

Section: Discussionmentioning

confidence: 99%

Classification of Muscle Invasive Bladder Cancer to Predict Prognosis of Patients Treated with Immunotherapy

Wang

et al. 2022

Journal of Immunology Research

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Background. Recently, immunotherapies have been approved for advanced muscle invasive bladder cancer (MIBC) treatment, but only a small fraction of MIBC patients could achieve a durable drug response. Our study is aimed at identifying tumor microenvironment (TME) subtypes that have different immunotherapy response rates. Methods. The mRNA expression profiles of MIBC samples from seven discovery datasets (GSE13507, GSE31684, GSE32548, GSE32894, GSE48075, GSE48276, and GSE69795) were analyzed to identify TME subtypes. The identified TME subtypes were then validated by an independent dataset (TCGA-MIBC). The subtype-related biomarkers were discovered using computational analyses and then utilized to establish a random forest predictive model. The associations of TME subtypes with immunotherapy therapeutic responses were investigated in a group of patients who had been treated with immunotherapy. A prognostic index model was constructed using the subtype-related biomarkers. Two nomograms were built by the subtype-related biomarkers or the clinical parameters. Results. Two TME subtypes, including ECM-enriched class (EC) and immune-enriched class (IC), were found. EC was associated with greater extracellular matrix (ECM) pathways, and IC was correlated with immune pathways, respectively. Overall survival was significantly greater for tumors classified as IC, whereas the EC subtype had a worse prognosis. A total of nine genes (AKAP12, APOL3, CXCL13, CXCL9, GBP4, LRIG1, PEG3, PODN, and PTPRD) were selected by computational analyses to construct the random forest model. The area under the curve (AUC) values for this model were 0.827 and 0.767 in the testing and external validation datasets, respectively. Therapeutic response rates were greater in IC patients than in EC patients (28 percent vs. 18 percent). Patients with a high prognostic index had a poorer prognosis than those with a low prognostic index. The nomogram constructed from nine genes and stage achieved a C-index of 0.71. Conclusion. The present investigation defined two distinct TME subtypes and developed models to assess immunotherapeutic treatment outcomes.

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Genomic and Gene Expression Studies Helped to Define the Heterogeneity of Small-Cell Lung Cancer and Other Lung Neuroendocrine Tumors and to Identify New Therapeutic Targets

Testa

Castelli

2022

Onco

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Small-cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma, corresponding to about 15% of lung cancers, occurring predominantly in smokers and associated with a very poor prognosis. Key genetic alterations very frequently observed in SCLC are represented by the loss of TP53 and RB1, due to mutational events or deletions; frequent amplification or overexpression of MYC family genes (MYC, MYCL and MYCN); frequent genetic alterations by mutation/deletion of KMT2D, RB family members p107 (RBL1) and p130 (RBL2), PTEN, NOTCH receptors and CREBBP. The profile of expression of specific transcription factors allowed to differentiate four subtypes of SCLC defined according to levels of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POUF23 (SCLC-P) or YAP1 (SCLC-Y). A recent study identified the subgroup SCLC-I, characterized by the expression of inflammatory/immune-related genes. Recent studies have characterized at molecular level other lung neuroendocrine tumors, including large cell neuroendocrine cancers (LCNECs) and lung carcinoids. These molecular studies have identified some therapeutic vulnerabilities that can be targeted using specific drugs and some promising biomarkers that can predict the response to this treatment. Furthermore, the introduction of immunotherapy (immune checkpoint blockade) into standard first-line treatment has led to a significant clinical benefit in a limited subset of patients.

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Impact of immune checkpoint gene CD155 Ala67Thr and CD226 Gly307Ser polymorphisms on small cell lung cancer clinical outcome

Cited by 3 publications

References 45 publications

CD155 mutation (Ala67Thr) increases the binding affinity for and the signaling via an inhibitory immunoreceptor TIGIT

CD155 mutation (Ala67Thr) increases the binding affinity for and the signaling via an inhibitory immunoreceptor TIGIT

Classification of Muscle Invasive Bladder Cancer to Predict Prognosis of Patients Treated with Immunotherapy

Genomic and Gene Expression Studies Helped to Define the Heterogeneity of Small-Cell Lung Cancer and Other Lung Neuroendocrine Tumors and to Identify New Therapeutic Targets

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