Immunotherapeutic Approaches for the Treatment of Colorectal Cancer

Абакушина, Е. В.; Gelm, Yu. V.; Пасова, И. А.; Bazhin, Alexandr V.

doi:10.1134/s0006297919070046

Cited by 15 publications

(10 citation statements)

References 46 publications

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“…Immunotherapy is now part of the standard treatment regimen for many solid tumours, 6 as the immune system is frequently dysregulated in cancer patients and inextricably linked with tumour growth 7 . Anti‐cancer immunotherapeutic approaches are classified into six categories: oncolytic virus therapy, adjuvant immunotherapy and cytokines, adoptive cell therapy, therapeutic vaccines, checkpoint inhibitors and monoclonal antibodies 8 . However, insufficient immune response has long been a concern, especially for checkpoint inhibitors targeting the programmed death 1 (PD‐1) and PD‐1 ligands (PD‐L1s) in CRC 9 .…”

Section: Introductionmentioning

confidence: 99%

“…7 Anti-cancer immunotherapeutic approaches are classified into six categories: oncolytic virus therapy, adjuvant immunotherapy and cytokines, adoptive cell therapy, therapeutic vaccines, checkpoint inhibitors and monoclonal antibodies. 8 However, insufficient immune response has long been a concern, especially for checkpoint inhibitors targeting the programmed death 1 (PD-1) and PD-1 ligands (PD-L1s) in CRC. 9 Especially, use of immune checkpoint inhibitors (ICIs) has little or no clinical activity in most metastatic CRC patients.…”

Section: Introductionmentioning

confidence: 99%

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A novel prognostic signature of immune‐related genes for patients with colorectal cancer

Wang

Chen

et al. 2020

J Cellular Molecular Medi

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Colorectal cancer (CRC) is one of the most commonly diagnosed cancers with an estimated 1.8 million new cases worldwide and associated with high mortality rates of 881 000 CRC‐related deaths in 2018. Screening programs and new therapies have only marginally improved the survival of CRC patients. Immune‐related genes (IRGs) have attracted attention in recent years as therapeutic targets. The aim of this study was to identify an immune‐related prognostic signature for CRC. To this end, we combined gene expression and clinical data from the CRC data sets of The Cancer Genome Atlas (TCGA) into an integrated immune landscape profile. We identified a total of 476 IRGs that were differentially expressed in CRC vs normal tissues, of which 18 were survival related according to univariate Cox analysis. Stepwise multivariate Cox proportional hazards analysis established an immune‐related prognostic signature consisting of SLC10A2 , FGF2 , CCL28 , NDRG1 , ESM1 , UCN , UTS2 and TRDC . The predictive ability of this signature for 3‐ and 5‐year overall survival was determined using receiver operating characteristics (ROC), and the respective areas under the curve (AUC) were 79.2% and 76.6%. The signature showed moderate predictive accuracy in the validation and GSE38832 data sets as well. Furthermore, the 8‐IRG signature correlated significantly with tumour stage, invasion, lymph node metastasis and distant metastasis by univariate Cox analysis, and was established an independent prognostic factor by multivariate Cox regression analysis for CRC. Gene set enrichment analysis (GSEA) revealed a relationship between the IRG prognostic signature and various biological pathways. Focal adhesions and ECM‐receptor interactions were positively correlated with the risk scores, while cytosolic DNA sensing and metabolism‐related pathways were negatively correlated. Finally, the bioinformatics results were validated by real‐time RT‑qPCR. In conclusion, we identified and validated a novel, immune‐related prognostic signature for patients with CRC, and this signature reflects the dysregulated tumour immune microenvironment and has a potential for better CRC patient management.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel prognostic signature of immune‐related genes for patients with colorectal cancer

Wang

Chen

et al. 2020

J Cellular Molecular Medi

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“…Apart from the surgical removal of the tumor, usually followed by adjuvant 5-fluoruracil (5-FU)-based chemotherapy, various immunotherapeutic approaches are currently being investigated as alternative options for the treatment of the disease (6,7). Latest encouraging developments in cancer immunotherapy, which involve priming the host's natural immune defenses to recognize, target and destroy cancer cells effectively, have brought some glimpse of hope for combatting CRC (8)(9)(10)(11). To this end, tremendous progress has been made in the understanding of the immune microenvironment of CRC (12).…”

Section: Introductionmentioning

confidence: 99%

High expression of immune checkpoints is associated with the TIL load, mutation rate and patient survival in colorectal cancer

2020

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Adoptive cell therapy with the use of tumorinfiltrating lymphocytes (TILs) is a very promising immunotherapeutic approach for the treatment of patients with colorectal cancer (CRC). However, within the tumor microenvironment, co-inhibitory immune checkpoints can inactivate TILs. The aim of the present study was to examine the association between the TIL load, the mutation rate and the clinical outcome in the immune landscape of patients with CRC. RNA-seq and whole exome seq data of 453 colon adenocarcinomas (COAD) and rectal adenocarcinomas (READ), along with the TIL load and clinicopathological information of each patient, were extracted from the TCGA GDC Data Portal and analyzed computationally. The expression of immune checkpoint molecules was compared between colon cancer and normal tissue. A total of 9 immune-related gene signatures were investigated in CRC. Spearman's correlation analysis was performed to examine the correlation between the TIL load with the expression of each immune checkpoint molecule. Indoleamine 2,3-dioxygenase 1 (IDO1) was found to be significantly overexpressed in CRC, whereas V-domain Ig suppressor of T cell activation (VISTA) and lymphocyte activating 3 (LAG3) were markedly downregulated. A high expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), IDO1, programmed cell death 1 (PD-1) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), tended to be associated with a better overall survival of the patients. In COAD, the TIL load positively correlated with the expression of adenosine A2A receptor (ADORA2A), CTLA-4, hepatitis A virus cellular receptor 2 (HAVCR2), lymphocyte activating 3 (LAG3), programmed death-ligand PD-L1, PD-L2, TIGIT and VISTA, whereas in READ, such positive correlations were noted only between the TIL load and LAG3 or PD-L2. The 'central memory T-cell' and 'exhausted T-cell' gene signatures were significantly lower among the READ tumors. The expression of PD-1, PD-L1, PD-L2, CTLA-4 and IDO1 was significantly higher among COAD patients with a high mutation rate (>34 mutations/Mb) compared to those with a lower rate. Somatic mutations in PD-1, PD-L1, CTLA-4 and other checkpoint molecules did not seem to affect their expression levels. On the whole, the data of the present study highlight the association of immune checkpoint molecules with the TIL load, patient survival and a high mutation rate in CRC. The data corroborate that patients with colon cancer with higher PD1, PD-L1/2, CTLA-4 and IDO1 expression, and a high mutation rate, are the ones who will benefit more from the respective immune checkpoint inhibition therapies.

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“…Thus, it is important to develop alternative treatments that can improve survival rate of colorectal cancer patients. One of such approaches is the development of cancer vaccine (Abakushina et al 2019;Bracci et al 2020;Wong-Arce et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Optimization of the human colorectal carcinoma antigen GA733-2 production in tobacco plants

Park

Kim

et al. 2021

Plant Biotechnol Rep

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The colorectal carcinoma-associated protein GA733-2 is one of the representative candidate protein for the development of plant-derived colorectal cancer vaccine. Despite of its significant importance for colorectal vaccine development, low efficiency of GA733-2 production limits its wide applications. To improve productivity of GA733-2 in plants, we here tested multiple factors that affect expression of recombinant GA733-2 (rGA733-2) and rGA733 fused to fragment crystallizable (Fc) domain (rGA733-Fc) protein. The rGA733-2 and rGA733-Fc proteins were highly expressed when the pBINPLUS vector system was used for transient expression in tobacco plants. In addition, the length of interval between rGA733-2 and left border of T-DNA affected the expression of rGA733 protein. Transient expression analysis using various combinations of Agrobacterium tumefaciens strains (C58C1, LBA4404, and GV3101) and tobacco species (Nicotiana tabacum cv. Xanthi nc and Nicotiana benthamiana) revealed that higher accumulation of rGA733-2 and rGA733-Fc proteins were obtained by combination of A. tumefaciens LBA4404 and Nicotiana benthamiana. Transgenic plants generated by introduction of the rGA733-2 and rGA733-Fc expression cassettes also significantly accumulated corresponding recombinant proteins. Bioactivity and stability of the plant-derived rGA733 and rGA733-Fc were evaluated by further in vitro assay, western blot and N-glycosylation analysis. Collectively, we here suggest the optimal condition for efficient production of functional rGA733-2 protein in tobacco system.

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Immunotherapeutic Approaches for the Treatment of Colorectal Cancer

Cited by 15 publications

References 46 publications

A novel prognostic signature of immune‐related genes for patients with colorectal cancer

A novel prognostic signature of immune‐related genes for patients with colorectal cancer

High expression of immune checkpoints is associated with the TIL load, mutation rate and patient survival in colorectal cancer

Optimization of the human colorectal carcinoma antigen GA733-2 production in tobacco plants

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