Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Abstract

The genomes of cancers deficient in mismatch repair (MMR) contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with MMR deficiency were sensitive to immune checkpoint blockade with anti-PD-1 antibodies. We have expanded this study to now evaluate efficacy of PD-1 blockade in patients with advanced MMR-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients and complete responses were achieved in 21% of patients. Responses were durable with median progression-free and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in MMR-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

Immunoprofiles of colorectal cancer from Lynch syndrome

“…PD-L1 expression have frequently been observed in MSI tumors with strong correlation to high levels of CD3 and CD8 positive cells. 12,14,28–30 In line with our results, PD-L1 expression are more frequently observed on immune cells at the invasive margin and rarely observed on tumor cells. 11,14,31 PD-L1 has been detected as a soluble ligand and may potentially be secreted by MMR deficient tumor cells.…”

“…The first studies have shown high degree of response in advanced-stage tumors, though patients with Lynch syndrome may have a somewhat lower response rate than patients with somatic MMR defects. 10-12 …”

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

“…However, PD-1 and PD-L1 blocking antibodies were proven unsuccessful in CRC, with the exception of MMR-deficient CRC. 23-25 , 27 , 28 The first aim of this study was to investigate whether the composition of the immune infiltrates and the intra-tumoral expression levels of inhibitory molecules in CRC metastases in the liver environment differ from those in primary CRC tumors and metastases outside the liver, which would suggest potential differences in sensitivity to checkpoint inhibitors among CRC tumors at different anatomical locations. The second objective was to determine whether targeting of inhibitory checkpoint pathways by antagonistic antibodies can enhance the functionality and anti-tumor responses of tumor-infiltrating T cells in LM-CRC.…”

“…22-25 In contrast, CRC patients hardly respond to PD-1 and PD-L1 blocking antibodies, 23-26 except for the minority of patients who are with mismatch repair (MMR)-deficient CRC. 27 , 28 A defective MMR enzyme system occurs in 10%-20% of CRC tumors and results in microsatellite instability, which is used as a molecular marker of MMR-deficiency. 29 It has been hypothesized that the observed difference in responsiveness to PD-1/PD-L1 blockade between MMR-deficient and MMR-proficient CRC is related to the higher numbers of somatic mutations in MMR-deficient tumors, due to the reduced ability to repair DNA damage.…”

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

“…5 However, objective responses were observed in only 53% of patients with deficient mismatch repair (dMMR) solid tumors and in 31% of distant metastatic CRC patients with high microsatellite instability (MSI-H). 6-8 The best candidates that benefit from immune checkpoint therapy are still unclear.…”