*MicroRNAs (miRNAs) in Colorectal Cancer DOI: http://dx.doi.org/10.5772/intechopen.80828*

*Oncogenes and Carcinogenesis*

*4.3.2 Immunotherapy*

survival in metastatic colorectal cancer patients receiving first-line oxaliplatinbased treatment [91]. The expression of miR-326 was related with decreased overall survival. These results proposed that plasma miRNAs can be used as noninvasive biomarkers for evaluating drug response in metastatic CRC patients who are treated

Since chemo/radio therapies and surgery have limitations, immunotherapy is a good alternative to treat CRC patients. Immunotherapy aimed to evoke immune system to eliminate tumors either using immune stimulatory cytokines (vaccines, etc.) or checkpoint inhibitors [such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 (PD-1) receptor, and its ligands (PD-L1/2)] [92]. Interestingly, immune cell filtrates more in MSI-high CRC, and these subtypes are

**miRNAs Therapy Expression Target genes** miR-7 EGFR-targeted Downregulate *EGFR*, *RAF-1*

miR-23a 5-FU Upregulate *APAF-1*, *ABCF-1*

miR-10b 5-FU Upregulate *BIM* miR-20a Oxaliplatin Upregulate *BNIP2* miR-21 5-FU Upregulate *MSH2* miR-22 5-FU Downregulate *BTG-1*

miR-27a, miR-27b 5-FU Downregulate *DPYD* miR-133b EGFR-targeted Downregulate *EGFR* miR-139-5p 5-FU Downregulate *Bcl-2* miR-143 Oxaliplatin Downregulate *IGF-1R* miR-153 Oxaliplatin Upregulate *FOXO3a* miR-199-5p, miR-375 EGFR Upregulate *PHLPP1* miR-203 5-FU Downregulate *TYMS* miR-203 Oxaliplatin Upregulate *ATM* miR-204 5-FU Downregulate *HMGA2* miR-218 5-FU Downregulate *TYMS*, *BIRC5* miR-302, miR-369, miR-200c 5-FU Upregulate *MRP8* miR-409-3p Oxaliplatin Downregulate *Beclin-1* miR-425-5p 5-FU Upregulate *PDCDIO* miR-494 5-FU Downregulate *DPYD* miR-519c 5-FU Downregulate *ABCG2*, *HuR*

miR-520g Oxaliplatin Upregulate *P21*

*Abbreviations: 5-FU, 5-fluorouracil; EGFR, epidermal growth factor; RAF-1, Raf protooncogene; BNIP2, BCL2 interacting protein 2; MSH2, human mutS homolog 2; BTG-1, BTG antiproliferation factor 1; APAF-1, apoptotic peptidase-activating factor 1; ABCF-1, ATP-binding cassette subfamily D member 1; DPYD, dihydropyrimidine dehydrogenase; Bcl-2, B cell lymphoma-2; IGF-1R, insulin-like growth factor 1 receptor; FOXO3a, forkhead box class O3; PHLPP1, Phlpp1 PH domain and leucine-rich repeat protein; TYMS, thymidylate synthase; ATM, ataxia telangiectasia mutated; HMGA2, high mobility group AT-hook 2; BIRC5, baculoviral IAP repeat containing 5; MRP8, myeloid-related protein 8; ABCG2, ATP-binding cassette subfamily G member 2; P21, cyclin-dependent* 

*The expression profile of miRNAs that have role on chemotherapy response in colorectal cancer (modified from* 

with 5-FU and oxaliplatin-based chemotherapy [91] (**Table 2**).

responding better to immunotherapies [93].

**38**

**Table 2.**

*Ref. [85]).*

*kinase inhibitor 1A.*

miRNAs are essential in regulation of the immune response as well. The role of miR-34 has been mentioned earlier. Upregulation of miR-34a elicits the activation of tumor-infiltrating CD8<sup>+</sup> T cells by targeting PD-L1 [94]. miRNAs are also involved in innate immunity by macrophages and NK cells, and adaptive immunity by B cells, T cells, and dendritic cells. miR-124 modulates signal transducer and activator of transcription 3 (STAT3) pathway and enhances the T cell-mediated immune clearance [95]. miR-491 regulates the proliferation and apoptosis of CD8<sup>+</sup> T cells [96]. miR-491 inhibits the activation of CD8<sup>+</sup> T cells and promotes its apoptosis via targeting B-cell lymphoma-extra-large (Bcl-xL), cyclin-dependent kinase-4 (CDK4), and T cell factor 1 (TCF1), hence aiding tumor cells escaping from immune system. Tumor-derived TGF-β also induces the miR-491 expression. Thus, miR-491 can be evaluated as a new immunotarget for CRC treatment [96].

miR-196b, miR-378a, and miR-486-5p are evaluated as predictive biomarkers for the efficacy of the vaccine treatment in CRC [97]. miRNAs were enrolled in Phase II studies. In 16 patients, high expression of miR-196b-5p and low expression of miR-378a-3p and miR-486-5p are associated with better prognosis after vaccine treatment. Hence, these miRNAs can be determined as novel biomarkers for prediction of outcome responses of patients [97].
