Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume -, Issue -, Pages -Publisher
SPRINGER
DOI: 10.1007/s00262-023-03520-5
Keywords
PD-L1; PD-1; Immune checkpoint inhibitor; Colorectal cancer; Immune therapy
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Colorectal cancer (CRC) is the second leading cause of cancer mortality. Most metastatic CRC cases have proficient mismatch repair and microsatellite stability. Programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) immune checkpoint inhibitors (ICIs) have been approved for the treatment of CRC patients with deficiency in mismatch repair (dMMR) and/or high microsatellite instability (MSI-H). However, CRC cases with proficient mismatch repair and microsatellite stability do not respond well to these inhibitors alone. Combination therapies are being investigated to enhance the anti-tumor response of PD-L1/PD-1 inhibitors in these patients.
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.
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