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Microsatellite Instability in Colorectal Cancers: Carcinogenesis, Neo-Antigens, Immuno-Resistance and Emerging

Violaine Randrian1,2, Camille Evrard3, David Tougeron1,2

  • 1Gastroenterology and Hepatology Department, Poitiers University Hospital, 86000 Poitiers, France.

Cancers
|July 2, 2021
PubMed

Insights

Deficient mismatch repair (dMMR) causes microsatellite instability (MSI), increasing tumor mutations and immune response. While effective, some metastatic colorectal cancers (mCRC) resist immune checkpoint inhibitors (ICI), necessitating new therapeutic strategies.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Deficient mismatch repair (dMMR) leads to microsatellite instability (MSI), characterized by a high tumor mutation burden.
  • MSI tumors can produce neo-antigens, stimulating anti-tumoral immune responses and good prognosis in non-metastatic disease.
  • Metastatic MSI tumors often exhibit immune escape, leading to poor prognosis, chemoresistance, and limited response to immune checkpoint inhibitors (ICI).

Purpose of the Study:

  • To review the mechanisms of carcinogenesis and immune activation in MSI tumors.
  • To explore hypotheses explaining primary and secondary resistance to ICI in dMMR/MSI metastatic colorectal cancer (mCRC).
  • To discuss emerging strategies for overcoming ICI resistance.

Main Methods:

  • Literature review focusing on dMMR, MSI, tumor immunology, and ICI resistance.
  • Analysis of carcinogenesis pathways and immune system activation by MSI.
  • Discussion of mechanistic hypotheses for ICI resistance and novel therapeutic approaches.

Main Results:

  • MSI drives neo-antigen production, enhancing anti-tumor immunity in early-stage disease.
  • Metastatic MSI tumors can evade immune surveillance, contributing to resistance and poor outcomes.
  • Primary and secondary resistance to ICI in dMMR/MSI mCRC is a significant clinical challenge.

Conclusions:

  • Understanding MSI-driven carcinogenesis and immune interactions is crucial for cancer therapy.
  • Identifying mechanisms of ICI resistance is key to developing more effective treatments for mCRC.
  • Novel strategies including targeting other checkpoints, vaccination, and microbiota modulation show promise for overcoming ICI resistance.
Keywords:
colorectal cancerdeficient mismatch repairimmune checkpoint inhibitorimmunotherapymicrobiotamicrosatellite instability

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