Abstract
Simple SummaryImmune checkpoint inhibitors have revolutionized the treatment landscape of microsatellite instable colorectal cancer. However, their efficacy is very limited in patients with microsatellite stable colorectal cancer. Recent preclinical and clinical studies have suggested the involvement of various tumor cell-intrinsic and tumor microenvironmental mechanisms in primary resistance to immunotherapy in microsatellite stable colorectal cancer. Because microsatellite stable colorectal cancers are immunologically heterogeneous with different immune evasive mechanisms, it is critical to precisely identify the major mechanism of resistance in each patient and to accordingly apply personalized combination immunotherapy strategies.Although immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of treating various malignancies, progress has been severely limited in metastatic colorectal cancer (mCRC). ICIs are effective in a fraction of patients with microsatellite instability-high mCRC but have little clinical efficacy in patients with microsatellite stable (MSS) mCRC, which accounts for 95% of mCRC cases. MSS mCRCs are considered to have intrinsic resistance to ICI monotherapy through multiple mechanisms. (1) They are poorly immunogenic because of their low tumor mutation burden; (2) frequent activation of the WNT/β-catenin signaling pathway excludes intratumoral CD8+ T cell immunity; (3) the tumor microenvironment is immunosuppressive because of the presence of various immunosuppressive cells, including tumor-associated macrophages and regulatory T cells; and (4) frequent liver metastasis in MSS mCRC may reduce the efficacy of ICIs. To overcome these resistance mechanisms, combination approaches using various agents, including STING agonists, MEK inhibitors, VEGF/R inhibitors, WNT/β-catenin inhibitors, oncolytic viruses, and chemo/radiotherapy, are actively ongoing. Preliminary evidence of the efficacy of some has been shown in early clinical trials. This review summarizes novel combination immunotherapy strategies described in recent preclinical and clinical studies to overcome the limitations of ICI monotherapy in MSS mCRC.
Highlights
Immunotherapy has revolutionized the treatment of MSI-H/dMMR metastatic colorectal cancer (mCRC) in the last five years; 95% of patients with mCRC have the microsatellite stable (MSS) subtype and have been left out of this breakthrough
MSS mCRC is refractory to immune checkpoint inhibitors (ICIs) therapy because of the lack of tumor antigens, exclusion of T cells by WNT/β-catenin activation, and Vascular endothelial growth factor (VEGF)-driven immunosuppressive tumor microenvironment (TME)
Attempts to overcome the resistance of MSS Colorectal cancer (CRC) to ICIs are currently ongoing with the combined administration of various therapeutics targeting Mitogen-activated protein/extracellular signal-regulated kinase (MEK), Stimulator of interferon (IFN) genes (STING), VEGF receptor (VEGFR), or WNT, or using oncolytic viruses
Summary
As representative agents for current cancer immunotherapy, immune checkpoint inhibitors (ICIs) have distinct mechanisms of action compared to traditional cytotoxic chemotherapy. In a phase II trial of pembrolizumab in patients with mCRC, the ORR was 40% in patients with MSI-H/dMMR mCRC, whereas no patients with MSS/pMMR showed an objective response [29]. We review the possible resistance mechanisms of immunotherapy and therapeutic targets for combination immunotherapy in MSS/pMMR mCRCs. mPFS, median progression-free survival; Pem, pembrolizumab; PD-1, programmed cell death-1; Nivo, nivolumab; Ipi, ipilimumab; CTLA-4, cytotoxic T lymphocyte antigen-4; Durva, durvalumab; Treme, tremelimumab; PD-L1, programmed cell death ligand-1; Cape, capecitabine; Beva, bevacizumab; Atezo, atezolizumab; VEGF, vascular endothelial growth factor; Rego, regorafenib; VEGFR, vascular endothelial growth factor receptor; Cobi, cobimetinib; MEK, mitogen-activated protein kinase kinase; Nivo*, 1 mg/kg plus 3 mg/kg; Nivo**, 3 mg/kg plus 1 mg/kg. Various tumor cell-intrinsic and microenvironmental factors mediate intrinsic resistance to immune checkpoint blockade in MSS/pMMR mCRC (Figure 1)
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