High IER5 Gene Expression Is Associated With Poor Prognosis in Glioma Patients

Available 4- and 5-year updates for progression-free and for overall survival demonstrate a lasting clinical benefit for melanoma patients receiving anti-PD-directed immune checkpoint inhibitor therapy. However, at least one-half of the patients either do not respond to therapy or relapse early or late following the initial response to therapy. Little is known about the reasons for primary and/or secondary resistance to immunotherapy and the patterns of relapse. This review, prepared by an interdisciplinary expert panel, describes the assessment of the response and classification of resistance to PD-1 therapy, briefly summarizes the potential mechanisms of resistance, and analyzes the medical needs of and therapeutic options for melanoma patients resistant to immune checkpoint inhibitors. We appraised clinical data from trials in the metastatic, adjuvant and neo-adjuvant settings to tabulate frequencies of resistance. For these three settings, the role of predictive biomarkers for resistance is critically discussed, as well as are multimodal therapeutic options or novel immunotherapeutic approaches which may help patients overcome resistance to immune checkpoint therapy. The lack of suitable biomarkers and the currently modest outcomes of novel therapeutic regimens for overcoming resistance, most of them with a PD-1 backbone, support our recommendation to include as many patients as possible in novel or ongoing clinical trials.

Section: Resistance In the Metastatic Settingmentioning

confidence: 99%

“…However, overall survival was not superior and toxicity was high with all patients in the TIL arm experiencing grade 4 adverse events [ 71 ]. Another Phase II study investigated the use of TIL in the PD-1 refractory setting [ 71 ]. This approach will be further proceeded with the intent of approval by the FDA.…”

Section: Resistance In the Metastatic Settingmentioning

confidence: 99%

Medical Needs and Therapeutic Options for Melanoma Patients Resistant to Anti-PD-1-Directed Immune Checkpoint Inhibition

Hassel

Zimmer

Sickmann

et al. 2023

“…A detailed depiction of the p53/IER5/HSF1 axis in normal cells and cancer cells is summarised in Figure 2 IER5 gene is negatively regulated by RNA polymerase II-associated factor 1 (PAF1), which binds to enhancers downstream of the IER5 promoter and hinders its transcription [70]. In addition to the p53-induced heat-shock response, IER5 was also reported to be associated with various other signalling pathways such as the KRAS and mTOR pathways and angiogenesis pathways [71]. IER5 expression has been shown to be increased in different experimental models in response to DNA damage, heat-shock, γ-irradiation, sleep IER5 gene is negatively regulated by RNA polymerase II-associated factor 1 (PAF1), which binds to enhancers downstream of the IER5 promoter and hinders its transcription [70].…”

Section: Ier5 Protects Normal and Cancer Cells From Stress Via P53/ie...mentioning

confidence: 99%

“…IER5 expression has been shown to be increased in different experimental models in response to DNA damage, heat-shock, γ-irradiation, sleep IER5 gene is negatively regulated by RNA polymerase II-associated factor 1 (PAF1), which binds to enhancers downstream of the IER5 promoter and hinders its transcription [70]. In addition to the p53-induced heat-shock response, IER5 was also reported to be associated with various other signalling pathways such as the KRAS and mTOR pathways and angiogenesis pathways [71]. IER5 expression has been shown to be increased in different experimental models in response to DNA damage, heat-shock, γ-irradiation, sleep deprivation, drugs like valproic acid, protein and peptide bound polysaccharides, etc.…”

Section: Ier5 Protects Normal and Cancer Cells From Stress Via P53/ie...mentioning

confidence: 99%

p53-Dependent Cytoprotective Mechanisms behind Resistance to Chemo-Radiotherapeutic Agents Used in Cancer Treatment

Krishnaraj¹,

Yamamoto²,

Ohki³

2023

Resistance to chemoradiotherapy is the main cause of cancer treatment failure. Cancer cells, especially cancer stem cells, utilize innate cytoprotective mechanisms to protect themselves from the adverse effects of chemoradiotherapy. Here, we describe a few such mechanisms: DNA damage response (DDR), immediate early response gene 5 (IER5)/heat-shock factor 1 (HSF1) pathway, and p21/nuclear factor erythroid 2–related factor 2 (NRF2) pathway, which are regulated by the tumour suppressor p53. Upon DNA damage caused during chemoradiotherapy, p53 is recruited to the sites of DNA damage and activates various DNA repair enzymes including GADD45A, p53R2, DDB2 to repair damaged-DNA in cancer cells. In addition, the p53-IER5-HSF1 pathway protects cancer cells from proteomic stress and maintains cellular proteostasis. Further, the p53-p21-NRF2 pathway induces production of antioxidants and multidrug resistance-associated proteins to protect cancer cells from therapy-induced oxidative stress and to promote effusion of drugs from the cells. This review summarises possible roles of these p53-regulated cytoprotective mechanisms in the resistance to chemoradiotherapy.

“…The transcriptional, clinical, and follow-up data of 298 patients with HGG were retrieved from the TCGA database (https://portal.gdc.cancer.gov/, accessed on 1 January 2023), while normal para-cancer samples were acquired from the GTEx database [16,17]. The corresponding medical imaging data were downloaded from TCIA (https://www.cancerimagingarchive.net/, accessed on 1 January 2023).…”

Section: Patients and Datasetsmentioning

confidence: 99%

Radiomics Features on Magnetic Resonance Images Can Predict C5aR1 Expression Levels and Prognosis in High-Grade Glioma

Wu,

Yang,

Zha

2023

Self Cite

Background: The complement component C5a receptor 1 (C5aR1) regulates cancer immunity. This retrospective study aimed to assess its prognostic value in high-grade glioma (HGG) and predict C5aR1 expression using a radiomics approach. Methods: Among 298 patients with HGG, 182 with MRI data were randomly divided into training and test groups for radiomics analysis. We examined the association between C5aR1 expression and prognosis through Kaplan–Meier and Cox regression analyses. We used maximum relevance–minimum redundancy and recursive feature elimination algorithms for radiomics feature selection. We then built a support vector machine (SVM) and a logistic regression model, investigating their performances using receiver operating characteristic, calibration curves, and decision curves. Results: C5aR1 expression was elevated in HGG and was an independent prognostic factor (hazard ratio = 3.984, 95% CI: 2.834–5.607). Both models presented with >0.8 area under the curve values in the training and test datasets, indicating efficient discriminatory ability, with SVM performing marginally better. The radiomics score calculated using the SVM model correlated significantly with overall survival (p < 0.01). Conclusions: Our results highlight C5aR1’s role in HGG development and prognosis, supporting its potential as a prognostic biomarker. Our radiomics model can noninvasively and effectively predict C5aR1 expression and patient prognosis in HGG.