Overcoming Tumor-Induced Immune Suppression to Improve Responses to Immunotherapy
Acute immune responses involving CD8+ cytotoxic T lymphocytes (CTLs) and/or natural killer cells can effectively restrain tumor development and progression. Unfortunately, immunotherapy attempts to date have struggled to achieve significant clinical benefit as single agents in PDAC. This is likely due to the presence of an immunosuppressive tumor microenvironment. Critical drivers of this immunosuppressive microenvironment are tumor-infiltrating inflammatory monocytes (IMs) and macrophages (TAMs). Thus, high numbers of these cells correlate with early metastatic relapse and poor survival in pancreatic cancer. Therefore, approaches that reprogram myeloid responses to potentiate protective antitumor immunity hold significant therapeutic potential.
Project 1 figure: CCR2 inhibition in human PDAC patients bolsters anti-tumor immunity but up-regulated the PD1/PDL1 checkpoint. A) Flowcytometry analyses of tumor FNA samples from PDAC patients in our CCR2 trial are depicted. Results are displayed as % of total cell. B) qRT-PCR analyses of tumors FNA samples. Results are displayed as relative percentage change of the post treatment sample (taken between cycle 2 and 3) compared to pre-treatment baseline sample (n=6 patients/treatment group). C) Representative plots from Flowcytometry on FNAs plot is gated on CD3+CD8+ T cells. Plot is representative of 6 patients accessed with similar effects.
We and other groups have demonstrated that mobilization and tumor infiltration of IMs and TAMs can promote local immunosuppression, and resistance to cytotoxic therapy. Signaling through C-C chemokine receptor type 2 (CCR2) is critical for the mobilization of IMs and their recruitment to inflamed tissues. Our recently published reports clearly illustrate that blockade of IM recruitment using a novel CCR2 inhibitor, PF-04136309 (CCR2i), slows tumor progression, improves responses to chemotherapy and prevents metastasis in mouse models of PDAC. Based on these exciting and provocative data, we initiated a Phase Ib/II clinical trial targeting the CCR2 signaling pathway in patients with locally advanced PDAC. In this trial, we have observed a remarkable 48.5% response rate in the 33 patients treated with CCR2i + FOLFIRINOX. Additionally, this regimen was well tolerated (safe). These responses appear to be correlated with a marked reduction in circulating CCR2+ IMs as well as decreased immune suppressive gene expression profiles in the primary tumor microenvironment. Paralleling these clinical data, our published pre-clinical studies found that CCR2 blockade overcomes immune suppression to reinitiate anti-tumor responses via CD8+ CTLs. Intriguingly, we’ve discovered that CCR2 blockade in both human patients and mouse models leads to the upregulation of T cell checkpoint pathways, including programmed cell death-1 (PD1) and its ligands. These data suggest that we might find unique therapeutic synergy between CCR2 inhibition and PD1-based immunotherapies.
Thus, our project 1 aims:
- Aim 1: Determine the effects of CCR2 blockade on T lymphocyte responses in patients with PC.
- Aim 2: Determine the mechanisms by which CCR2 inhibition improves T cell immunity
- Aim 3: Determine whether combining CCR2 inhibition with PD1 blockade can enhance therapeutic outcomes in patients with advanced PC.
Our research will assess the safety and efficacy of targeting CCR2 to improve PD1-based immunotherapy. At the same time, we will improve our understanding of the mechanism(s) by which CCR2 blockade improves CTL responses in humans and mice.