Intrinsic resistance and efficacy of immunotherapy in microsatellite instability-high colorectal cancer: A systematic review and meta-analysis

Abstract

Some patients with microsatellite instability-high colorectal cancer (MSI-H CRC) have shown a poor response to immunotherapy in clinical trials. We investigated the intrinsic resistance to and efficacy of immunotherapy in patients with MSI-H CRC. The PubMed and Web of Science databases were searched using keywords such as “colorectal cancer,” “immunotherapy,” and “clinical experiment.” Random-effects models were used to generate the combined complete response, partial response, stable disease, progressive disease, objective response rate (ORR), disease control rate (DCR), and incidence of adverse events. We then performed a subgroup analysis based on the ORR and incidence of intrinsic resistance. The meta-analysis included seven clinical trials. The incidences of complete response, partial response, stable disease, and progressive disease summarized by the random-effects model were 8%, 37%, 26%, and 25%, respectively. The ORR and DCR were 45% and 71%, respectively. The ORRs of programmed cell death protein 1 inhibitor (anti-PD-1), programmed death ligand 1 inhibitor (anti-PD-L1), and anti-PD-1 combined with cytotoxic T lymphocyte-associated antigen 4 inhibitor (anti-CTLA-4) immunotherapy were 38%, 54%, and 57%, respectively. The ORR of immune checkpoint inhibitors for first- and third-line therapy was 56% and 32%, respectively. Dual-drug immunotherapy significantly reduced the incidence of intrinsic resistance to immunotherapy (12% vs 31%). The incidences of intrinsic resistance to first-line therapy and second-line and later therapy were 29% and 26%, respectively. Approximately 25% of patients with MSI-H CRC had intrinsic resistance to immunotherapy. Anti-PD-1 combined with anti-CTLA-4 significantly increased the ORR, thereby reducing the incidence of intrinsic resistance. Moving immunotherapy into earlier lines of therapy, although not reducing the incidence of intrinsic resistance, can improve the ORR in patients with MSI-H CRC.

Microsatellite Instability: A Review of Molecular Epidemiology and Implications for Immune Checkpoint Inhibitor Therapy

“…As previously shown, a significant proportion of MSI patients do not respond to ICI therapy. About 25% of MSI CRC cases have intrinsic resistance to immunotherapy [ 43 ]. Several mechanisms have been proposed to explain this observation.…”

“…Overall, the objective response rate (ORR) for tumors with MSI varies between 34% and 69% depending on the line of therapy, while the rate of pathologic complete response (pCR) may reach 100% in neoadjuvant settings, which indicates a high efficacy of checkpoint inhibitors in MSI tumors [ 40 , 41 , 42 ]. At the same time, about a quarter of metastatic colorectal cancers and up to half of some other types of cancer are intrinsically resistant to ICI [ 43 , 44 ]. Several mechanisms of such an intrinsic resistance have been proposed, including the activating mutations in the RAS/RAF signaling pathway [ 45 ], mutations in the antigen presentation machinery and interferon pathway genes [ 46 , 47 ], establishment of an immunosuppressive microenvironment [ 48 ], as well as the influence of the gut microbiome [ 49 ] and immunoediting theory [ 50 ].…”

Identification of colon cancer subtypes based on multi-omics data—construction of methylation markers for immunotherapy

“…However, the detection rate of dMMR or MSI-H only accounts for 5%-10% in colon cancers ( 6 , 7 ). Additionally, approximately 25% of detected patients do not benefit from immunotherapy ( 8 ). It is worth noting that some patients with microsatellite stability (MSS) also experienced prolonged OS after immunotherapy ( 9 ).…”

Identification of 8 candidate microsatellite instability loci in colorectal cancer and validation of the ACVR2A mechanism in the tumor progression

“…Accurate detection of dMMR or MSI tumors is thus pivotal for enhancing cancer screening, diagnosis, and individualized treatment planning 4 . Clinical trials have consistently shown that MSI-H tumor patients respond more favorably to anti-PD-1/PD-L1 therapy 5 , 6 . The development of targeted therapeutics, including chimeric antibodies, multi-kinase inhibitors, and precision drugs, has enabled the selective inhibition of dysregulated signaling pathways in cancer cells 7 , 8 .…”