Project Summary:
The overall survival of colorectal cancer (CRC) patients has improved significantly over the past few decades,
but the 5-year survival rate for patients with stage IV CRC remains below 14%. Therefore, there is an urgent
need to develop more effective and safer treatments against CRC. New immune checkpoint inhibitor (ICI)
therapies have ushered in a new era of immunotherapy and emerged as important treatment options for a variety
of solid tumors. However, ICIs are only effective in CRC patients with deficient mismatch repair (dMMR) and
microsatellite instability-high (MSI-H). For the approximately 85% of CRC patients who carry proficient mismatch
repair (pMMR) and microsatellite stable (MSS) or instability-low (MSI-L) CRCs, ICIs show little clinical benefit. In
a preliminary study, we examined the efficacy of low-dose sulindac in enhancing the response of pMMR/MSS
CRC to anti-PD-L1 immunotherapy. Utilizing a syngeneic mouse tumor model and a humanized patient-derived
xenograft (PDX) mouse model, we compared the inhibitory effects of PD-L1 antibodies (Abs), sulindac at low
doses, and their combination on pMMR/MSS CRC. Our results demonstrated that the mice treated with the
combination therapy showed a significant reduction in tumor volume, along with an increase of CD8+ tumor-
infiltrating lymphocytes (TILs) in tumor tissues. While studying the mechanism of action, we found that sulindac
could transcriptionally inhibit PD-L1 expression and ultimately reduce the release of exosomal PD-L1 into the
circulation. As exosomal PD-L1 normally binds to and depletes circulating PD-L1 Abs, the combination of
sulindac and the PD-L1 Ab can potentially enhance antibody recruitment. Therefore, we hypothesize that low-
dose sulindac can sensitize CRC to anti-PD-L1 therapy. In this application, we propose three specific aims to
systematically and rigorously investigate this new activity of sulindac. In Aim 1, we will study the mechanisms by
which sulindac sensitizes CRC to anti-PD-L1 therapy, specifically how sulindac regulates PD-L1 expression; in
Aim 2, we will use innovative and robust humanized PDX models to study the in vivo efficacy of low-dose sulindac
in enhancing anti-PD-L1 therapy. Both MSS and MSI CRC models will be tested. In Aim 3, we will investigate
whether the combination of sulindac and anti-PD-L1 therapy can block the metastatic progression of CRC. Since
sulindac and PD-L1 antibodies are FDA-approved drugs and their safety and toxicity profiles have been well-
documented, we hope that the success of our study will rapidly facilitate Phase II clinical trials to investigate the
utility of sulindac-enhanced anti-PD-L1 therapy in CRC and address the important clinical challenge of poor
response to ICI therapy in the majority of CRC patients.