Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside

Darleny Y. Lizardo, Chaoyuan Kuang, Suisui Hao, Jian Yu, Yi Huang, Lin Zhang

Research output: Contribution to journalReview articlepeer-review

11 Scopus citations

Abstract

Colorectal cancers (CRCs) with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) often have sustained responses to immune checkpoint inhibitors (ICIs) including selective monoclonal antibodies against Program Death 1 (PD-1), Programmed Death Ligand 1(PD-L1), and cytotoxic T lymphocyte associated antigen 4 (CTLA-4). However, a substantial fraction of dMMR CRCs do not respond or ultimately develop resistance to immunotherapy. The majority (~85%) of CRCs are MMR proficient (pMMR) or microsatellite stable (MSS) and lack response to ICIs. Understanding the biology and mechanisms underlying dMMR-associated immunogenicity is urgently needed for improving the therapeutic efficacy of immunotherapy on CRC. Compared to pMMR/MSS CRCs, dMMR/MSI CRCs typically have increased tumor mutational burden (TMB), lower response rate to 5-fluorouracil-based chemotherapy, distinctive immunological features such as high tumor-infiltrating lymphocytes (TILs), and better prognosis. Here, we review the current understanding of the clinical relevance of dMMR/MSI in CRCs, the molecular basis and rationales for targeting dMMR CRC with immunotherapy, and clinical approaches using ICIs as single agents or in combination with other therapies for MSI-H CRCs. Furthermore, we address the potential strategies to sensitize pMMR/MSS CRC to immunotherapy by converting an immunologically “cold” microenvironment into a “hot” one.

Original languageEnglish (US)
Article number188447
JournalBiochimica et Biophysica Acta - Reviews on Cancer
Volume1874
Issue number2
DOIs
StatePublished - Dec 2020
Externally publishedYes

Keywords

  • Colorectal cancer
  • Combination therapy
  • Immune checkpoint inhibitors
  • Immunotherapy
  • Microsatellite instability
  • Mismatch repair deficiency

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

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