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PD-1 and PD-L1 inhibitors in cold colorectal cancer: challenges and strategies. Cancer Immunol Immunother 2023 Dec;72(12):3875-3893

Date

10/13/2023

Pubmed ID

37831146

Pubmed Central ID

PMC10700246

DOI

10.1007/s00262-023-03520-5

Scopus ID

2-s2.0-85174215652 (requires institutional sign-in at Scopus site)   5 Citations

Abstract

Colorectal cancer (CRC) is the second most common cause of cancer mortality, with mismatch repair proficient (pMMR) and/or microsatellite stable (MSS) CRC making up more than 80% of metastatic CRC. Programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) immune checkpoint inhibitors (ICIs) are approved as monotherapy in many cancers including a subset of advanced or metastatic colorectal cancer (CRC) with deficiency in mismatch repair (dMMR) and/or high microsatellite instability (MSI-H). However, proficient mismatch repair and microsatellite stable (pMMR/MSS) cold CRCs have not shown clinical response to ICIs alone. To potentiate the anti-tumor response of PD-L1/PD-1 inhibitors in patients with MSS cold cancer, combination strategies currently being investigated include dual ICI, and PD-L1/PD-1 inhibitors in combination with chemotherapy, radiotherapy, vascular endothelial growth factor (VEGF) /VEGF receptor (VEGFR) inhibitors, mitogen-activated protein kinase (MEK) inhibitors, and signal transducer and activation of transcription 3 (STAT3) inhibitors. This paper will review the mechanisms of PD-1/PD-L1 ICI resistance in pMMR/MSS CRC and potential combination strategies to overcome this resistance, summarize the published clinical experience with different combination therapies, and make recommendations for future avenues of research.

Author List

Lin KX, Istl AC, Quan D, Skaro A, Tang E, Zheng X

Author

Alexandra C. Istl MD, MPH Assistant Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

B7-H1 Antigen
Colonic Neoplasms
Colorectal Neoplasms
Humans
Microsatellite Instability
Programmed Cell Death 1 Receptor
Rectal Neoplasms
Vascular Endothelial Growth Factor A