Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects

Makaremi, Shima; Asadzadeh, Zahra; Hemmat, Nima; Baghbanzadeh, Amir; Sgambato, Alessandro; Ghorbaninezhad, Farid; Safarpour, Hossein; Argentiero, Antonella; Brunetti, Oronzo; Bernardini, Renato; Silvestris, Nicola; Baradaran, Behzad

doi:10.3390/biomedicines9091075

Cited by 56 publications

(46 citation statements)

References 225 publications

(289 reference statements)

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“…The existing therapeutic options have failed to provide an appropriate response in PDAC, reinforcing the unlucky privilege of being one of the deadliest cancers worldwide ( Latenstein et al, 2020 ). Regrettably, even immunotherapy, which has recently revolutionized the drug regimes in cancer treatment ( Makaremi et al, 2021 ), has shown few successful chances in PDAC due to tumor-related stroma abundance ( Panchal et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers. Albeit its incidence does not score among the highest in cancer, PDAC prognosis is tremendously fatal. As a result of either aggressiveness or metastatic stage at diagnosis, chemotherapy constitutes the only marginally effective therapeutic approach. As gemcitabine (Gem) is still the cornerstone for PDAC management, the low response rate and the onset of resistant mechanisms claim for additional therapeutic strategies. The first synthetic orally active adiponectin receptor agonist AdipoRon (AdipoR) has recently been proposed as an anticancer agent in several tumors, including PDAC. To further address the AdipoR therapeutic potential, herein we investigated its pharmacodynamic interaction with Gem in human PDAC cell lines. Surprisingly, their simultaneous administration revealed a more effective action in contrasting PDAC cell growth and limiting clonogenic potential than single ones. Moreover, the combination AdipoR plus Gem persisted in being effective even in Gem-resistant MIA PaCa-2 cells. While a different ability in braking cell cycle progression between AdipoR and Gem supported their cooperating features in PDAC, mechanistically, PD98059-mediated p44/42 MAPK ablation hindered combination effectiveness. Taken together, our findings propose AdipoR as a suitable partner in Gem-based therapy and recognize the p44/42 MAPK pathway as potentially involved in combination outcomes.

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Section: Discussionmentioning

confidence: 99%

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

et al. 2022

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“…Immunotherapy is a promising method in cancer treatment and has achieved remarkable efficacy in the treatment of colorectal cancer (Ganesh et al, 2019). Due to the high heterogeneity of molecular genetics and histopathology of colon cancer, immunotherapy still has limitations and obstacles (Makaremi et al, 2021). TME plays a crucial role in the tumorigenesis and progression of COAD, and the immunosuppressive function is one of the causes of poor response to treatment.…”

Section: Discussionmentioning

confidence: 99%

Identification of Hypoxia-Related Subtypes, Establishment of Prognostic Models, and Characteristics of Tumor Microenvironment Infiltration in Colon Cancer

Wang

Tang

et al. 2022

Front. Genet.

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Background: Immunotherapy is a treatment that can significantly improve the prognosis of patients with colon cancer, but the response to immunotherapy is different in patients with colon cancer because of the heterogeneity of colon carcinoma and the complex nature of the tumor microenvironment (TME). In the precision therapy mode, finding predictive biomarkers that can accurately identify immunotherapy-sensitive types of colon cancer is essential. Hypoxia plays an important role in tumor proliferation, apoptosis, angiogenesis, invasion and metastasis, energy metabolism, and chemotherapy and immunotherapy resistance. Thus, understanding the mechanism of hypoxia-related genes (HRGs) in colon cancer progression and constructing hypoxia-related signatures will help enrich our treatment strategies and improve patient prognosis.Methods: We obtained the gene expression data and corresponding clinical information of 1,025 colon carcinoma patients from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, respectively. We identified two distinct hypoxia subtypes (subtype A and subtype B) according to unsupervised clustering analysis and assessed the clinical parameters, prognosis, and TME cell-infiltrating characteristics of patients in the two subtypes. We identified 1,132 differentially expressed genes (DEGs) between the two hypoxia subtypes, and all patients were randomly divided into the training group (n = 513) and testing groups (n = 512). Following univariate Cox regression with DEGs, we construct the prognostic model (HRG-score) including six genes (S1PR3, ETV5, CD36, FOXC1, CXCL10, and MMP12) through the LASSO–multivariate cox method in the training group. We comprehensively evaluated the sensitivity and applicability of the HRG-score model from the training group and the testing group, respectively. We explored the correlation between HRG-score and clinical parameters, tumor microenvironment, cancer stem cells (CSCs), and MMR status. In order to evaluate the value of the risk model in clinical application, we further analyzed the sensitivity of chemotherapeutics and immunotherapy between the low-risk group and high-risk group and constructed a nomogram for improving the clinical application of the HRG-score.Result: Subtype A was significantly enriched in metabolism-related pathways, and subtype B was significantly enriched in immune activation and several tumor-associated pathways. The level of immune cell infiltration and immune checkpoint-related genes, stromal score, estimate score, and immune dysfunction and exclusion (TIDE) prediction score was significantly different in subtype A and subtype B. The level of immune checkpoint-related genes and TIDE score was significantly lower in subtype A than that in subtype B, indicating that subtype A might benefit from immune checkpoint inhibitors. Finally, an HRG-score signature for predicting prognosis was constructed through the training group, and the predictive capability was validated through the testing group. The survival analysis and correlation analysis of clinical parameters revealed that the prognosis of patients in the high-risk group was significantly worse than that in the low-risk group. There were also significant differences in immune status, mismatch repair status (MMR), and cancer stem cell index (CSC), between the two risk groups. The correlation analysis of risk scores with IC50 and IPS showed that patients in the low-risk group had a higher benefit from chemotherapy and immunotherapy than those in the high-risk group, and the external validation IMvigor210 demonstrated that patients with low risk were more sensitive to immunotherapy.Conclusion: We identified two novel molecular subgroups based on HRGs and constructed an HRG-score model consisting of six genes, which can help us to better understand the mechanisms of hypoxia-related genes in the progression of colon cancer and identify patients susceptible to chemotherapy or immunotherapy, so as to achieve precision therapy for colon cancer.

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“…According to our new method, NG2/CSPG4-expressing cells can be isolated not only from normal adult solid organ tissues [ 22 ] but cancerous ones as well, and these expanded cultures could better support studies on novel immunotherapies targeting membrane NG2/CSPG4 either with antibodies or vaccines. Additionally, the success of antibodies targeting programmed cell death protein 1 (PD-1) and its ligand L1 (PD-L1) in solid organ cancer treatment and the need for improving response frequency could lead to an increased demand for the development of combination therapies with anti-PD-1/PD-L1 blockers as a backbone [ 78 , 79 , 80 , 81 ].…”

Section: Selection Of Ng2/cspg4 As a Target Antigen For The Treatment...mentioning

confidence: 99%

Immunotherapeutic Targeting of NG2/CSPG4 in Solid Organ Cancers

Zhang

et al. 2022

Vaccines

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: Neuro-glia antigen 2/chondroitin sulfate proteoglycan 4 (NG2/CSPG4, also called MCSP, HMW-MAA, MSK16, MCSPG, MEL-CSPG, or gp240) is a large cell-surface antigen and an unusual cell membrane integral glycoprotein frequently expressed on undifferentiated precursor cells in multiple solid organ cancers, including cancers of the liver, pancreas, lungs, and kidneys. It is a valuable molecule involved in cancer cell adhesion, invasion, spreading, angiogenesis, complement inhibition, and signaling. Although the biological significance underlying NG2/CSPG4 proteoglycan involvement in cancer progression needs to be better defined, based on the current evidence, NG2/CSPG4+ cells, such as pericytes (PCs, NG2+/CD146+/PDGFR-β+) and cancer stem cells (CSCs), are closely associated with the liver malignancy, hepatocellular carcinoma (HCC), pancreatic malignancy, and pancreatic ductal adenocarcinoma (PDAC) as well as poor prognoses. Importantly, with a unique method, we successfully purified NG2/CSPG4-expressing cells from human HCC and PDAC vasculature tissue blocks (by core needle biopsy). The cells appeared to be spheres that stably expanded in cultures. As such, these cells have the potential to be used as sources of target antigens. Herein, we provide new information on the possibilities of frequently selecting NG2/CSPG4 as a solid organ cancer biomarker or exploiting expressing cells such as CSCs, or the PG/chondroitin sulfate chain of NG2/CSPG4 on the cell membrane as specific antigens for the development of antibody- and vaccine-based immunotherapeutic approaches to treat these cancers.

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Immune Checkpoint Inhibitors in Colorectal Cancer: Challenges and Future Prospects

Cited by 56 publications

References 225 publications

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

Identification of Hypoxia-Related Subtypes, Establishment of Prognostic Models, and Characteristics of Tumor Microenvironment Infiltration in Colon Cancer

Immunotherapeutic Targeting of NG2/CSPG4 in Solid Organ Cancers

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