Identification of DNA mismatch repair molecular signatures that predict response to immune checkpoint blockade.
Abstract
Despite showing great clinical promise, response rates to immune checkpoint blockade
(ICB) vary greatly and biomarkers of response are lacking. A recent Phase II clinical trial
in patients with deficiency in the DNA mismatch repair (MMR) pathway indicated that
MMR-deficient status predicted clinical benefit with the PD-1 inhibitor, pembrolizumab.
These findings have led to the first tissue-agnostic approval for anti PD-1 therapy for
unresectable or metastatic solid tumours with MMR deficiency. However, it is becoming
increasingly clear that many MMR-deficient tumours fail to respond to ICBs with ~50%
refractory to treatment. Furthermore, there is a wide diversity of clinical benefit among
responders. However why this is the case and how this can be clinically translated
remains largely unknown. Our exciting preliminary data suggest that loss of specific
MMR genes results in a differential increased expression of the immune checkpoint
molecule, PD-L1. Significantly, we observed an upregulation of PD-L1 expression in cells
silenced for the MMR genes, MLH1, MSH2 and PMS2, as expected. However, we did not
observe an increased expression of PD-L1 upon MSH6 loss. This differential expression
amongst MMR gene loss was validated at the protein, RNA and cell surface level in a
range of human and murine cell lines. Upon investigation of the molecular mechanism
regulating PD-L1 expression after MMR loss, we observed that that phosphorylation of
STAT1 positively correlates with PD-L1 expression whilst STAT3 phosphorylation was
negatively correlated, such that increased STAT1 phosphorylation was observed upon
MLH1, MSH2 and PMS2 loss and not in MSH6-deficient cells whilst STAT3
phosphorylation was only observed upon MSH6 loss. Significantly, inhibition of STAT3,
both pharmacologically and genetically, reinstated PD-L1 expression in MSH6-deficient
cells. Therefore, we have evidence that loss of specific MMR genes can trigger
differential expression of PD-L1 through a STAT1/STAT3 mediated pathway and we
hypothesize that it is this differential expression that may in part determine sensitivity
to treatment with ICB.
Authors
Smith., Charlotte.Collections
- Theses [4235]