Genetic diversity of tumors with mismatch repair deficiency influences anti–PD-1 immunotherapy response

Abstract

Tumors with mismatch repair deficiency (MMR-d) are characterized by sequence alterations in microsatellites and can accumulate thousands of mutations. This high mutational burden renders tumors immunogenic and sensitive to programmed cell death–1 (PD-1) immune checkpoint inhibitors. Yet, despite their tumor immunogenicity, patients with MMR-deficient tumors experience highly variable responses, and roughly half are refractory to treatment. We present experimental and clinical evidence showing that the degree of microsatellite instability (MSI) and resultant mutational load, in part, underlies the variable response to PD-1 blockade immunotherapy in MMR-d human and mouse tumors. The extent of response is particularly associated with the accumulation of insertion-deletion (indel) mutational load. This study provides a rationale for the genome-wide characterization of MSI intensity and mutational load to better profile responses to anti–PD-1 immunotherapy across MMR-deficient human cancers.

Optimizing Patient Outcomes with PD‐1/PD‐L1 Immune Checkpoint Inhibitors for the First‐Line Treatment of Advanced Non–Small Cell Lung Cancer

“…Tumor mutational burden (TMB) is a measure of somatic nonsynonymous mutations quantitated using next‐generation sequencing . High TMB is associated with microsatellite instability and DNA mismatch repair deficiency, and high levels of tumor neoantigens that may be indicative of interactions between immune cells and tumor cells that may respond to immunotherapy .…”

“…Tumor mutational burden (TMB) is a measure of somatic nonsynonymous mutations quantitated using next‐generation sequencing . High TMB is associated with microsatellite instability and DNA mismatch repair deficiency, and high levels of tumor neoantigens that may be indicative of interactions between immune cells and tumor cells that may respond to immunotherapy . A meta‐analysis of eight controlled and uncontrolled studies evaluated the association between TMB and ICI response in 2661 patients with NSCLC (six trials), urothelial carcinoma (one trial), and other solid tumors (one trial) .…”

“…35 High TMB is associated with microsatellite instability and DNA mismatch repair deficiency, and high levels of tumor neoantigens that may be indicative of interactions between immune cells and tumor cells that may respond to immunotherapy. 35 A meta-analysis of eight controlled and uncontrolled studies evaluated the association between TMB and ICI response in 2661 patients with NSCLC (six trials), urothelial carcinoma (one trial), and other solid tumors (one trial). 36 The immunotherapy regimens included nivolumab plus ipilimumab (three trials), nivolumab (one trial), atezolizumab (two trials), pembrolizumab (one trial), and various ICIs (one trial) as first-or second-line therapy.…”

Relatively semi-conservative replication and a folded slippage model for simple sequence repeats

“…The occurrence of SSRs will possibly encounter selective pressure, though it may be different in coding or non-coding regions, then, we use f i representing the fixation possibility of the newly born repeats facing with the selective pressure. The f i = 0 when the occurrences of new repeats are the lethal mutations and unable fixation in the organism, or may be excluded by DNA repair system (Jeggo et al, 2015;Mandal et al, 2019). The fixation coefficient is 0<f i <1 when the new SSRs are the deleterious but fixed in the genome within alive individuals, like Huntington's disease (Macdonald et al, 1993).…”

“…Simple sequence repeats (SSRs), also referred as microsatellites, have attracted increasingly great interests in recent decades (Chen et al, 2010;Ellegren, 2004;Mandal et al, 2019;Morgante et al, 2002;Vinces et al, 2009a;Zhao et al, 2012), and have been widely analyzed in the genome sequences of eukaryotic prokaryotic and also viral genomes (Ellegren, 2004;Lin & Kussell, 2012;Morgante et al, 2002;Zhao et al, 2012). SSRs are the most variable genomic sequences, which tend to appear frequent variations in repeat-unit number instead of nucleotide substitution.…”