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Immunotherapy Response in MMR-Deficient Tumors Linked to MSI Levels, Indel Mutations

NEW YORK (GenomeWeb) – Response to anti-PD-1 checkpoint blockade immunotherapy in tumors with mismatch repair (MMR) defects depends on a tumor's overall mutational load and its level of microsatellite instability, as well as the relative proportion of small insertion and deletion (indel) mutations, new research in mouse models and human samples suggests.

"The human-based and murine evidence … demonstrates that the genome-wide intensity of microsatellite instability and resultant tumor mutational load influence response to anti-PD-1 immunotherapy and tumor evolution in MMR-deficient tumors," corresponding author Timothy Chan of Memorial Sloan Kettering Cancer Center  and his colleagues wrote in a Science paper published online today. "The basis of this response is likely multifactorial and may disproportionately rely on indel mutations over missense mutations to drive clinical outcome."

Researchers from MSK, Johns Hopkins University and elsewhere used CRISPR-Cas9 gene editing to produce mouse cell line models of melanoma or colon carcinoma that were missing the MSH2 gene, passaging them over time to get lines marked by both MMR deficiency and varying levels of microsatellite instability, as quantified with the MSIsensor algorithm.

"This approach enabled us to compare responses to anti-PD-1 immunotherapy in isogenic cell line-derived systems that differed only in MSI intensity levels and resultant mutational loads," the authors explained. "Both MSI-intermediate and MSI-high cell lines lack functional MMR protein machinery and possess statistically higher proportions of unstable microsatellites compared to the unedited parental lines."

By tallying the single base variants, indels, and other alterations in these cell lines compared with the pre-passage parental cell lines, for example, the team saw an expected rise in non-synonymous single base and indel changes in the MSI-high lines. But somewhat more surprisingly, the MMR-deficient mouse cell line cancer models took on new indels more often than new missense single nucleotide variants as microsatellite instability progressed from MSI-intermediate to MSI-high.

Likewise, the researchers reported that MMR-deficient mouse lines implanted into mice were more apt to respond to anti-PD-1 antibody treatment as microsatellite instability increased, while MSI-intermediate and parental lines showed little response. They noted that T cell infiltration was also enhanced in the mice with MSI-high tumors compared to the MSI-intermediate and parental tumor models — an effect that corresponded with the rise in new coding indels in the tumors and enhanced immune pathway expression with advancing microsatellite instability.

When the team took a closer look at the tumor alterations that remained after anti-PD-1 treatment, meanwhile, it saw signs that immune editing preferentially plucked out tumor cells with indels that arose while the MMR-deficient tumors were shifting toward increasing microsatellite instability, rather than alterations present at baseline in the parental cell lines.

Based on these and other results, the authors suggested that "indel mutations may have a greater likelihood of generating an immunogenic response over missense mutations in these tumors." Indeed, their subsequent analysis of transcriptome and exome sequences for 14 human cancers previously profiled for the Cancer Genome Atlas project shored up the notion that more MSI-high versions of MMR-deficient tumors had increased immune cell infiltration and better patient responses to treatment.

Again, that was particularly true of cases with higher indel mutational loads, the researchers reported. In a handful of MMR-deficient cases of colorectal cancer, esophageal cancer, or gastric cancer, for example, they found that microsatellite stability levels discerned with the MSK-IMPACT targeted sequencing test and MSIsensor algorithm seemed to line up with checkpoint blockade immunotherapy response. 

The authors cautioned that their study was not intended to hammer out microsatellite instability or indel mutation thresholds for predicting immunotherapy responses. Even so, they wrote, the mouse and human data considered in their analyses "demonstrate that in multiple independent cohorts of MMR-[deficient] human patients treated with checkpoint blockade, a range of relative MSI phenotypes exists and may help identify patients who will derive clinical benefit from immunotherapy."

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