TY - JOUR
T1 - Immunotherapy efficacy on mismatch repair-deficient colorectal cancer
T2 - From bench to bedside
AU - Lizardo, Darleny Y.
AU - Kuang, Chaoyuan
AU - Hao, Suisui
AU - Yu, Jian
AU - Huang, Yi
AU - Zhang, Lin
N1 - Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
KW - Colorectal cancer
KW - Combination therapy
KW - Immune checkpoint inhibitors
KW - Immunotherapy
KW - Microsatellite instability
KW - Mismatch repair deficiency
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U2 - 10.1016/j.bbcan.2020.188447
DO - 10.1016/j.bbcan.2020.188447
M3 - Review article
C2 - 33035640
AN - SCOPUS:85092654244
SN - 0304-419X
VL - 1874
JO - Biochimica et Biophysica Acta - Reviews on Cancer
JF - Biochimica et Biophysica Acta - Reviews on Cancer
IS - 2
M1 - 188447
ER -