Abstract
This study performed a comprehensive molecular characterization of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal (GI) tumors to elucidate predictors of response to PD-1 blockade. Forty-five patients with MSI-H/dMMR GI tumors, including gastric cancer, colorectal cancer, cholangiocarcinoma, small intestine cancer, pancreatic cancer, and duodenal cancer, receiving PD-1 blockade were analyzed. We conducted the genomic profiling of GI tumors by whole-exome sequencing or targeted next-generation sequencing. The tumor microenvironment was evaluated by transcriptomic analysis and multiplex fluorescence IHC. Patients with low tumor mutational burdens (TMBs) had lower objective response rates (ORRs; 0% vs. 48.8%) and a significantly shorter progression-free survival (PFS; 2.3 vs. 15.6 months; HR, 6.20; P = 0.002) than those with high TMBs. Among common gene alterations in GI tumors, only PTEN mutations, which were mutually exclusive with a low TMB, were significantly associated with a lower ORRs than wild-type PTEN (21.4 vs. 54.8%; odds, 4.45; P = 0.045). Compared with wild-type PTEN, PTEN mutations in the phosphatase domain were associated with significantly lower ORRs (12.5 vs. 54.8%; P = 0.049), shorter PFS (2.6 vs. 15.6 months; HR, 5.04; P < 0.001), lower intratumoral CD8+ T-cell levels, higher intratumoral CD204+ macrophage levels, and PI3K/AKT/mTOR pathway enrichment, whereas PTEN mutations in the C2 domain were not. Low TMBs and PTEN mutations, especially mutations in the phosphatase domain associated with an immunosuppressive environment, were mutually exclusive and might be negative predictors of PD-1 blockade responses in patients with MSI-H/dMMR GI tumors.
Highlights
Microsatellite instability–high (MSI-H) or mismatch repair– deficient tumors exhibit frequent mutations in multiple genes, contributing to the enhanced expression of neoantigens, increased CD8þ T-cell infiltration, and expression of related immune checkpoint molecules in the tumor microenvironment [1, 2]
Among common gene alterations in GI tumors, only PTEN mutations, which were mutually exclusive with a low tumor mutational burdens (TMBs), were significantly associated with a lower objective response rates (ORRs) than wildtype PTEN (21.4 vs. 54.8%; odds, 4.45; P 1⁄4 0.045)
Compared with wild-type PTEN, PTEN mutations in the phosphatase domain were associated with significantly lower ORRs (12.5 vs. 54.8%; P 1⁄4 0.049), shorter progression-free survival (PFS) (2.6 vs. 15.6 months; HR, 5.04; P < 0.001), lower intratumoral CD8þ T-cell levels, higher intratumoral CD204þ macrophage levels, and PI3K/AKT/ mTOR pathway enrichment, whereas PTEN mutations in the C2 domain were not
Summary
Microsatellite instability–high (MSI-H) or mismatch repair– deficient (dMMR) tumors exhibit frequent mutations in multiple genes, contributing to the enhanced expression of neoantigens, increased CD8þ T-cell infiltration, and expression of related immune checkpoint molecules in the tumor microenvironment [1, 2]. Immune checkpoint inhibitors, such as PD-1 blockade, have shown improved survival outcomes in patients with MSI-H or dMMR gastrointestinal. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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