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COMMENTARY
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Mismatch repair mutations: Biomarker for immunotherapy in colorectal cancers


 Department of Surgery, Kansas City VA Medical Center, University of Missouri, Kansas City, USA

Date of Submission25-May-2020
Date of Decision08-Oct-2020
Date of Acceptance22-Oct-2020
Date of Web Publication07-Aug-2021

Correspondence Address:
Santosh Shenoy,
Department of Surgery, Kansas City VA Medical Center, University of Missouri, Kansas City
USA
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_548_20

PMID: 34380860




How to cite this URL:
Shenoy S. Mismatch repair mutations: Biomarker for immunotherapy in colorectal cancers. Indian J Cancer [Epub ahead of print] [cited 2021 Sep 28]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=323438




Cancers with defective DNA mismatch repair (dMMR) genes contain mutations most frequently located on microsatellite regions and are defined as microsatellite instability (MSI) tumors. dMMR-mutated colon cancers have special characteristics such as right colon predilection, poorly differentiated histology, presence of mucin, and lymphocytic infiltration.[1] In addition, dMMR mutations together with tumor mutational burden (TMB) and checkpoint receptor expressions such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1) and its ligand (PD-L1) also play an important role as a predictive biomarker for immunotherapy. This brief commentary elaborates on the mechanisms and predictive relevance of dMMR mutations as a biomarker for immunotherapy in advanced colon cancers.

MMR genes maintain the fidelity of DNA replication and genomic integrity. These genes encode for proteins that form DNA MMR complexes. They correct small base insertions or deletions that may occur during somatic division. Thus MMR system proofreads and repairs defects that were overlooked by DNA polymerase.[2]

Methylation-associated epigenetic silencing of these genes leads to transcription and translation of abnormal peptides. These peptides are called neoantigens and are recognized by immune cells as nonself antigens. Neoantigens in tumors contribute to increased infiltration by cytotoxic T-lymphocytes (TIL) and express immune checkpoint ligands which are hallmarks of many solid malignancies such as colon cancers, endometrial, gastric cancers, melanoma and non-small cell lung cancers, etc.[3]

The presence of TIL in the tumor is considered to be a favorable prognostic factor. Studies performed on MMR deficient mice with colorectal cancer cells have demonstrated an increased mutational load and neoantigens profile, and with improved survival due to immune surveillance by TILs.[4]

High-tumor mutation burden i.e., increased neoantigens resulting in increased TIL infiltration, has emerged as a favorable predictive marker of responsiveness to immunotherapy. The initial human trials were performed by Le et al. on MMR-mutated patients with metastatic colorectal cancer treated with pembrolizumab (anti-PD-1). The data demonstrated improved progression-free and overall survival when compared to MMR stable patients.[5] In contrast, tumors that are microsatellite-stable (MSS) or MSI-low displayed a low TIL infiltration (immune desert phenomenon) and failed to respond to immune checkpoint blockade therapy.[6]

However, response to immunotherapy is inconsistent and tumors develop evasive, immune escape responses by adaptive mechanisms leading to T-cell anergy, exhaustion, and inactivation. Tumor cells stimulate and elaborate coinhibitory T-cell surface receptors known as PD-1 and CTLA-4 and their ligands. These receptors are also known as immune checkpoint receptors [Figure 1].[3]
Figure 1: The figure is created by the author of this manuscript. The complex interplay between tumor cell (red), APC (green), cytotoxic tumor-infiltrating lymphocyte (TIL) in blue color. Endogenous peptides (tumor neoantigens) are processed and presented on the MHC class I molecules on tumor cells and class II molecules on APC. T-cell-neoantigens interaction and costimulatory activity are required for effective T-cell-mediated killing. PD1 and CTLA-4 receptors (pink) with respective ligands PDL-1 and B7 (pink) inhibit this co-stimulation and cause T-cell inactivation (anergy, exhaustion)

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PD-1 and its ligands PD-L1 and PD-L2 are peripheral immune checkpoints on the tumor, stromal, and immune cells, while CTLA-4 and CD28 and its costimulatory ligands B7-1/B7-2 on antigen-presenting cells. Both PD-1 and CTLA-4 preferentially bind to their respective ligands to suppress excessive T-cell activity. These negative signals are important in normal physiological homeostasis to maintain immune tolerance, tune down the immune response after elimination of the pathogen, and to prevent damaging normal tissue (autoimmunity). Tumor cells take advantage of this phenomenon to create immune tolerance and evade immune destruction.[3] Preventing the inhibitory activity of the PD-1 and CTLA-4 receptors by immune checkpoint blockers activates the cytotoxic activity of the TIL. The discovery of this mechanism (inhibition of negative immune regulation) is the basis of immune checkpoint targeted therapy to enhance host-immune surveillance and tumor destruction. Dr. James P. Allison and Dr. Tasuku Honjo were awarded the Nobel Prize for physiology and medicine in the year 2018 for these discoveries which have since revolutionized the field of immunotherapy in cancer.

For colorectal cancers, immune checkpoint blockade with drugs such as pembrolizumab and nivolumab (anti-PD1 antibodies) and combination of nivolumab with the anti-CTLA-4 antibody ipilimumab has received the United States Food and Drug Administration (FDA) regulatory approval for the treatment of refractory, metastatic tumors that are MMR deficient or have high levels of microsatellite instability (MSI-H).[6] Recently in July 2020, pembrolizumab was also approved as a first-line treatment for patients with unresectable or metastatic MSI-H, MMR deficient tumors in the United States. This was based on a large multicenter, international, randomized control trial (NCT02563002) comparing pembrolizumab with standard chemotherapy treatment in 308 patients with MSI-H, MMR deficient tumors. The study demonstrated a statistically significant improvement in progression-free survival (PFS). Median PFS was 16.5 months in the pembrolizumab group and 8.2 months in the standard chemotherapy cohort. Long-term analysis of this data is currently being assessed.[7]

Given the surge and success of immune checkpoint blockade therapy, certain caveats should be emphasized. Not all patients with MMR/MSI-H mutation-positive tumors respond to the therapy. Both primary and secondary resistance has been observed and factors that predict resistance are currently being evaluated.[6] Secondly, immune-checkpoint blockade has its own set of unique adverse events. This immune-related antitumor response may cause autoimmune-like adverse side effects (irAE), especially severe when a combination of both anti-PD1 antibodies and anti-CTLA-4 antibody is instituted.[6],[8] Common organ systems involved are skin (dermatitis, eczema, vitiligo), gastrointestinal (diarrhea, colitis, a flare-up of inflammatory bowel disease), pulmonary (pneumonitis), endocrine (thyroiditis, adrenal insufficiency, hypophysitis), hepatic (autoimmune hepatitis), and renal (acute kidney injury).[6],[8] The majority of these irAE can be managed with early identification and conservative medical therapies.

To conclude, DNA MMR mutations in tumors contain abnormalities that affect the DNA repair mechanisms and remain a useful predictive biomarker in advanced colon cancers and for a response to immunotherapy. There are currently other ongoing investigations with other checkpoint inhibitors and its efficacy in metastatic, adjuvant, and neoadjuvant settings as first-line therapy and combination with other upcoming modalities.[6] These clinical trials and details can be accessed at the ClinicalTrials.gov database.



 
  References Top

1.
Paulose RR, Ail DA, Biradar S, Vasudevan A, Sundaram KR. Prognostic and predictive significance of microsatellite instability in stage II colorectal carcinoma: An 8-year study from a tertiary center in South India. Indian J Cancer 2019;56:302-8.  Back to cited text no. 1
[PUBMED]  [Full text]  
2.
Hsieh P. Molecular mechanisms of DNA mismatch repair. Mutat Res 2001;486:71-87.  Back to cited text no. 2
    
3.
Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 2018;8:1069-86.  Back to cited text no. 3
    
4.
Germano G, Lamba S, Rospo G, Barault L, Magrì A, Maione F, et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 2017;552:116-20.  Back to cited text no. 4
    
5.
Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-20.  Back to cited text no. 5
    
6.
Ganesh K, Stadler ZK, Cercek A, Mendelsohn RB, Shia J, Segal NH, et al. Immunotherapy in colorectal cancer: Rationale, challenges and potential. Nat Rev Gastroenterol Hepatol 2019;16:361-75.  Back to cited text no. 6
    
7.
8.
Morse MA, Overman MJ, Hartman L, Khoukaz T, Brutcher E, Lenz HJ, et al. Safety of nivolumab plus low-dose ipilimumab in previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer. Oncologist 2019;2411:1453-61.  Back to cited text no. 8
    


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