Strategy to targeting the immune resistance and novel therapy in colorectal cancer

Abstract

Assessing the CRC subtypes that can predict the outcome of colorectal cancer (CRC) in patients with immunogenicity seems to be a promising strategy to develop new drugs that target the antitumoral immune response. In particular, the disinhibition of the antitumoral T-cell response by immune checkpoint blockade has shown remarkable therapeutic promise for patients with mismatch repair (MMR) deficient CRC. In this review, the authors provide the update of the molecular features and immunogenicity of CRC, discuss the role of possible predictive biomarkers, illustrate the modern immunotherapeutic approaches, and introduce the most relevant ongoing preclinical study and clinical trials such as the use of the combination therapy with immunotherapy. Furthermore, this work is further to understand the complex interactions between the immune surveillance and develop resistance in tumor cells. As expected, if the promise of these developments is fulfilled, it could develop the effective therapeutic strategies and novel combinations to overcome immune resistance and enhance effector responses, which guide clinicians toward a more "personalized" treatment for advanced CRC patients.

Keywords: Colorectal cancer; gene phenotype; immune resistance; immunotherapy; subtypes.

Figure 1

Consensus molecular subtypes (CMS) of CRC subtypes are associated with specific clinical outcomes. CRC is currently classified into four CMS. CMS1 is also called MSI‐like, indicative of hypermutations, and microsatellite unstable features which generally accompany strong immune activation (microsatellite instability immune, 14%). The CMS1 is also enriched for tumors with a CIMP and mutations in the BRAF oncogene; CMS2 (canonical, 37%) is a subtype with high chromosomal instability (CIN), showed epithelial characters and marked WNT and MYC signaling activation; CMS3 (metabolic, 13%) is enriched in tumors with KRAS mutations and shows epithelial characters and metabolic dysregulation, and KRAS‐mutated CRC is highly heterogeneous at the gene expression level, with unique metabolic dependencies in tumors with a CMS3‐dominant phenotype; CMS4 (mesenchymal, 23%) has a mesenchymal phenotype and frequent CIMP phenotype and shows stromal infltration, strong angiogenic features, and hyperactivation of transforming growth factors (TGF‐β).

Figure 2

The immune profiles and immune pathways in CRC subtypes. CMS1 is defined by upregulated immune pathways with upregulated Th1 lymphocyte, cytotoxic T cell, NK cell infiltration, and upregulated immune checkpoints such as PD‐1. CMS2 demonstrates upregulation of canonical pathways including WNT and MYC downstream targets. CMS3 is defined by upregulation of metabolic pathways including fatty acid oxidation. CMS4 is the mesenchymal subtype displaying upregulated EMT pathways, TGF‐β signaling, matrix remodeling, angiogenesis, complement activation, integrin‐β3 upregulation, stromal infiltration, and immune upregulation.

Figure 3

Targeting therapy for CMS1,2,4 phenotype in RAS wild‐type CRC. In CMS1 subtypes of CRC, the reduced expression of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) is linked to hypermethylation of the ligands' promoter regions. In CMS2 phenotype, frequently overexpress EGFR ligands and harbor amplifications of EGFR and IRS2, which are markers of cetuximab sensitivity. However, the resistance to EGFR mAbs in RAS wild‐type patients is also enriched in the CMS2 population, making it the most appealing group to test combinations of pan‐ERBB and IGF1R inhibitors. Indeed, both UFO and NOTCH networks pathways are overactive in CMS4 mesenchymal CRC. The combination of chemotherapy with a TGF‐β receptor (TGFR) inhibitor has tested positive for a “TGF‐β activated” signature as part of project in metastatic CRC. The effort to discover the potential targets that may increase the efficacy of EGFR mAbs in the RAS wild‐type CMS4 population includes drivers of EMT and treatment resistance, such as MET and integrins, and combination therapy with cetuximab and a mAb anti‐integrin‐αv was particularly effective in patients whose tumors displayed high integrin‐αvβ6 expression levels in CMS4 mesenchymal samples.

Figure 4

The potential targets for mutated KRAS metabolic CMS3 phenotype in CRC. KRAS and BRAF may contribute to colorectal cancer, display increased expression of the primary glucose transporter SLC2A1 (GLUT‐1), and exhibit a Warburg effect phenotype, with the increased glucose consumption rate and concomitant increased lactate production rate in isogenic colorectal cancer cells. Therefore, the global energy metabolism of CRC cells could be controlled by KRAS mutations to promote glucose uptake, while the control toward Warburg effect is critical to connect tumor cells with complex genetic changes, such as PI3K, AKT, Myc, HIF‐1, p53. The role of LDH‐A in the invasive colorectal cancers to maintain an efficient glycolysis in glycolytic phenotype and the LDH level correlates with the change in overall tumor burden in CRC. Remarkably, high‐dose vitamin C has been shown to impair CRC tumor growth in mouse models by causing oxidative stress mediated the increased uptake of the oxidized vitamin C through GLUT‐1 and this inhibited glycolysis at glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) to result in an energy crisis and ultimately cell death.

Figure 5

The immune resistance and immunotherapy in MSI‐high CRC. The high degree of microsatellite instability (MSI—high) in CRC is associated with intense T‐cell infiltration, caused by mismatch repair defects in MSI‐high tumor frameshift mutations and truncated protein (neopeptides), causing antitumor T‐cell‐mediated adaptive immunity. Immunotherapy with PD‐1 therapy has potential benefit for immunogenic MSI‐H CRCs whereas there is no evidence to date to suggest immunotherapy benefit in MSS CRCs. Tumor cells may escape immune surveillance by acquiring different genetic alterations, a higher expression of mesenchymal transition genes, immunosuppressive genes, and chemokines that recruit immunosuppressive cells may be associated with innate anti‐PD‐1 resistance. Likewise, high tumor PGE2 expression represents a key mediator of immune resistance, mainly due to the secretion of suppressive chemokines and the recruitment of MDSCs, which results in immunogenic loss.

Figure 6

Regulation of the antitumor T‐cell immunity‐mediated TGF‐β in CRC. The pro‐tumorigenic functions of TGF‐β are mediated not only through direct action on tumor cells but also through its effects on immune cells—inhibition of CTLs, TH1 cells, and NK cells, and expansion of Treg cells, B cells, and MDSCs. CTLs can be found in the tumor core or in the tumor margin. The positive treatment outcome was associated with an expansion of tumor‐infiltrating effector CTLs and TH1 cells, enhanced antitumor T‐cell immunity. Alternative immunotherapeutic approaches to be explored in inflamed TGF‐β‐mediated mesenchymal tumors include pharmacological elimination of MDSCs or blockade of related immunosuppressive chemokine signaling circuits and pathways in an immune‐evasive microenvironment.