Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer

Abstract

BackgroundPancreatic cancer is characterised by the accumulation of a fibro-inflammatory stroma. Within this stromal reaction, myeloid cells are a predominant population. Distinct myeloid subsets have been correlated with tumour promotion and unmasking of anti-tumour immunity.ObjectiveThe goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer and to understand the relationship between myeloid cells and T cell-mediated immunity within the pancreatic cancer microenvironment.MethodsPrimary mouse pancreatic cancer cells were transplanted into CD11b-diphtheria toxin receptor (DTR) mice. Alternatively, the iKras* mouse model of pancreatic cancer was crossed into CD11b-DTR mice. CD11b+ cells (mostly myeloid cell population) were depleted by diphtheria toxin treatment during tumour initiation or in established tumours.ResultsDepletion of myeloid cells prevented KrasG12D-driven pancreatic cancer initiation. In pre-established tumours, myeloid cell depletion arrested tumour growth and in some cases, induced tumour regressions that were dependent on CD8+ T cells. We found that myeloid cells inhibited CD8+ T-cell anti-tumour activity by inducing the expression of programmed cell death-ligand 1 (PD-L1) in tumour cells in an epidermal growth factor receptor (EGFR)/mitogen-activated protein kinases (MAPK)-dependent manner.ConclusionOur results show that myeloid cells support immune evasion in pancreatic cancer through EGFR/MAPK-dependent regulation of PD-L1 expression on tumour cells. Derailing this crosstalk between myeloid cells and tumour cells is sufficient to restore anti-tumour immunity mediated by CD8+ T cells, a finding with implications for the design of immune therapies for pancreatic cancer.

Strategies for Increasing Pancreatic Tumor Immunogenicity

“…Thus inhibition of immunosuppression, rather than immune activation alone, is critical to achieve durable clinical responses. Consistent with this, CTLA-4 and PD-pathway expression are upregulated in PDAC (43–45), and both are associated with worse survival (44,46). Furthermore, PD-1 is expressed on multiple PDAC infiltrating T cell subsets, including Tregs, and CD4 + and CD8 + effector T cells (37).…”

Cancer and inflammation

“…This results in tumor regression and greatly improves patient outcomes (Figure 3g) (110, 121). Importantly, myeloid derived cells recruited by the inflammatory process express PD-L1 and are involved in the immunosuppression (9, 124, 127). Current research in many labs and clinics is focused on further understanding and improving upon this strategy to “wake up” the immune system in other indications, and in patients who are refractory to anti-PD-1 treatment.…”

Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development

“…Inhibiting the CCR2-CCL2 axis modulates both T and non-T cell immune mechanisms, potentially leading to enhanced response in combination with cytotoxic chemotherapy (74). Intriguingly, it appears that myeloid cell depletion is crucial to inducing durable anti-tumor immune responses (73,74,77). With increasing immunotherapies becoming available and entering clinical trials, there is an urgent need to identify biomarkers of response to stratify patients to effective immunotherapy combinations at appropriate time-points in the tumor life-span.…”