In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies

Ieranò, Caterina; Righelli, Dario; D’Alterio, Crescenzo; Napolitano, Maria; Portella, Luigi; Rea, Giuseppina; Auletta, Federica; Santagata, Sara; Trotta, Anna Maria; Guardascione, Giuseppe; Liotti, Federica; Prevete, Nella; Maiolino, Piera; Luciano, Antonio; Barbieri, Antônio; Mauro, Annabella Di; Roma, Cristin; Abate, Riziero Esposito; Tatangelo, Fabiana; Pacelli, Roberto; Normanno, Nicola; Melillo, Rosa Marina; Scala, Stefania

doi:10.1136/jitc-2021-004032

Cited by 37 publications

(33 citation statements)

References 46 publications

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“…Quiescent cancer cells resist T‐cell attack by forming an immunosuppressive niche in primary breast cancer 53 . A very recent total RNA‐seq study revealed that in PD‐1+ human colon cancer cells, tumor survival pathways activation and up‐regulation of DCAF13 expression were observed after being treated with anti‐PD‐1 nivolumab (NIVO), suggesting DCAF13 may affect the patient's response to immune checkpoint suppression therapy as an immunosuppressor in colon cancer 54 . Our findings suggest that targeting DCAF13 inhibition may be a possibility to alter the immune microenvironment and enhance immunotherapeutic efficacy.…”

Section: Discussionmentioning

confidence: 99%

A multidimensional pan‐cancer analysis of DCAF13 and its protumorigenic effect in lung adenocarcinoma

Wei

Xing

et al. 2023

The FASEB Journal

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DCAF13 is a substrate recognition protein in the ubiquitin‐proteasome system with oncogenic effects in several malignant tumors. However, it is unclear that the relationship between DCAF13 expression pattern and prognosis across different cancer types. Also unknown is the biological function or effects on the immune microenvironment of DCAF13. In this study, we parsed multiple public databases to explore the potential tumorigenic actions of DCAF13, including correlations with prognosis, microsatellite instability (MSI), tumor mutational burden (TMB), immune checkpoint genes, immune cell infiltration, and immunotherapy response in pan‐cancer. Moreover, we validated DCAF13 expression in a tissue microarray by immunohistochemistry and investigate its effects in vitro and in vivo. The results showed that DCAF13 was upregulated in 17 cancer types and correlated with poor prognosis in many cancers. Also, the correlation between DCAF13 and TMB was found in 14 cancers as well as MSI in nine. The expression level of DCAF13 was found to be notably correlated with immune cell infiltration, showing a negative correlation with CD4 T cell infiltration and a positive correlation with neutrophil infiltration. The oncogene DCAF13 expression was shown to have a positive correlation with CD274 or ADORA2A and negative correlation with VSIR, TNFRSF4, or TNFRSF14 across large subsets of human cancers. Finally, we observed that DCAF13 was highly expressed in a tissue microarray of lung cancer. In immunocompromised mouse models, xenograft growth of human lung cancer cells was significantly inhibited by DCAF13 knockdown. Our results highlighted the value of DCAF13 as a promising independent predictor of poor prognosis through numerous biological processes. High DCAF13 expression often predicts suppressive immune microenvironment and immunotherapy resistance in a pan‐cancer context.

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Section: Discussionmentioning

confidence: 99%

A multidimensional pan‐cancer analysis of DCAF13 and its protumorigenic effect in lung adenocarcinoma

Wei

Xing

et al. 2023

The FASEB Journal

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“…Additionally, ICIs targeting PD-1, PD-L1, or CTLA4 have enabled the possibility of long-term survival in patients with tumors such as melanoma, HCC, breast cancer, and colorectal cancer ( 47 , 48 ). Previous studies demonstrated that tumor cell-intrinsic ICGs regulated tumor development ( 34 , 49 , 50 ). Therefore, correlations between CRGs and ICGs at the mRNA level were investigated and discussed in our study.…”

Section: Discussionmentioning

confidence: 99%

Copper and cuproptosis-related genes in hepatocellular carcinoma: therapeutic biomarkers targeting tumor immune microenvironment and immune checkpoints

et al. 2023

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BackgroundHepatocellular carcinoma (HCC), one of the most common cancers worldwide, exhibits high immune heterogeneity and mortality. Emerging studies suggest that copper (Cu) plays a key role in cell survival. However, the relationship between Cu and tumor development remains unclear.MethodsWe investigated the effects of Cu and cuproptosis-related genes (CRGs) in patients with HCC in the TCGA-LIHC (The Cancer Genome Atlas-Liver cancer, n = 347) and ICGC-LIRI-JP (International Cancer Genome Consortium-Liver Cancer-Riken-Japan, n = 203) datasets. Prognostic genes were identified by survival analysis, and a least absolute shrinkage and selection operator (Lasso) regression model was constructed using the prognostic genes in the two datasets. Additionally, we analyzed differentially expressed genes and signal pathway enrichment. We also evaluated the effects of CRGs on tumor immune cell infiltration and their co-expression with immune checkpoint genes (ICGs) and performed validation in different tumor immune microenvironments (TIMs). Finally, we performed validation using clinical samples and predicted the prognosis of patients with HCC using a nomogram.ResultsA total of 59 CRGs were included for analysis, and 15 genes that significantly influenced the survival of patients in the two datasets were identified. Patients were grouped by risk scores, and pathway enrichment analysis suggested that immune-related pathways were substantially enriched in both datasets. Tumor immune cell infiltration analysis and clinical validation revealed that PRNP (Prion protein), SNCA (Synuclein alpha), and COX17 (Cytochrome c oxidase copper chaperone COX17) may be closely correlated with immune cell infiltration and ICG expression. A nomogram was constructed to predict the prognosis of patients with HCC using patients’ characteristics and risk scores.ConclusionCRGs may regulate the development of HCC by targeting the TIM and ICGs. CRGs such as PRNP, SNCA, and COX17 could be promising targets for HCC immune therapy in the future.

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“…The patients with high-risk scores might be more sensitive to ICIs responses and Elesclomol, Indoximod, nivolumab and Pazopanib had a treatment advantage in the high-risk group. ICIs can effectively treat advanced MSI-H tumors and MSI-H can be used as a biomarker for treatment ( 55 ). The present study hypothesized that the proportion of patients with MSI-H was higher in the high-risk group.…”

Section: Discussionmentioning

confidence: 99%

Construction of cuproptosis‑associated prognostic signature in colon adenocarcinoma based on bioinformatics and RT‑qPCR analysis

2023

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Colon adenocarcinoma (COAD) is the most common pathological subtype of colon cancer with a high degree of malignancy. Cuproptosis is a newly discovered copper-dependent cell death pattern distinguished from all the other known programmed cell death. Hence, it can be used as a potential therapeutic target for cancer. The present study aimed to clarify the relationship between cuproptosis and prognosis of COAD. The variations of 12 cuproptosis-associated genes based on 623 patients with COAD were comprehensively identified. It was found that 8 out of 12 were differentially expressed in tumors and normal tissues and CDKN2A showed a higher prognostic value. Therefore, two molecular subtypes were explored and the subtype A, with higher expression of cuproptosis-associated genes, showed more enrichment of immune pathways and survival advantage over those with lower cuproptosis-associated genes expression. The risk score and a nomogram predicting pattern were constructed to quantify a single patient and the risk score could serve as an independent prognostic factor by multivariate Cox regression analysis (P<0.001, HR: 1.350, 95% CI: 1.189-1.534). The expression levels of key prognostic genes (PMM2, ACOX1, KDM3A, HSPB1, PPARGC1A, UPK3B and EPHB2) was analyzed by HCT-116 colon cancer cells and HT-29 colorectal cancer cells using reverse transcription-quantitative PCR. The high-risk group, characterized by higher immune infiltration, increased microsatellite instability-high, high tumor mutation burden and high expression level of immune checkpoints, indicated higher drug sensitivity. In conclusion, our analysis confirms the potential role of cuproptosis-associated genes in the prognosis of COAD and it will provide new ideas for immunotherapy.

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In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies

Cited by 37 publications

References 46 publications

A multidimensional pan‐cancer analysis of DCAF13 and its protumorigenic effect in lung adenocarcinoma

A multidimensional pan‐cancer analysis of DCAF13 and its protumorigenic effect in lung adenocarcinoma

Copper and cuproptosis-related genes in hepatocellular carcinoma: therapeutic biomarkers targeting tumor immune microenvironment and immune checkpoints

Construction of cuproptosis‑associated prognostic signature in colon adenocarcinoma based on bioinformatics and RT‑qPCR analysis

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