Abstract
Despite the availability of recently developed chemotherapy regimens, survival times for pancreatic cancer patients remain poor. These patients also respond poorly to immune checkpoint blockade therapies (anti-CTLA-4, anti-PD-L1, anti-PD-1), which suggests the presence of additional immunosuppressive mechanisms in the pancreatic tumour microenvironment (TME). CD40 agonist antibodies (αCD40) promote antigen presenting cell (APC) maturation and enhance macrophage tumouricidal activity, and may therefore alter the pancreatic TME to increase sensitivity to immune checkpoint blockade. Here, we test whether αCD40 transforms the TME in a mouse syngeneic orthotopic model of pancreatic cancer, to increase sensitivity to PD-L1 blockade. We found that whilst mice bearing orthotopic Pan02 tumours responded poorly to PD-L1 blockade, αCD40 improved overall survival. αCD40 transformed the TME, upregulating Th1 chemokines, increasing cytotoxic T cell infiltration and promoting formation of an immune cell-rich capsule separating the tumour from the normal pancreas. Furthermore, αCD40 drove systemic APC maturation, memory T cell expansion, and upregulated tumour and systemic PD-L1 expression. Combining αCD40 with PD-L1 blockade enhanced anti-tumour immunity and improved overall survival versus either monotherapy. These data provide further support for the potential of combining αCD40 with immune checkpoint blockade to promote anti-tumour immunity in pancreatic cancer.
Highlights
Tumours employ a number of mechanisms to escape detection and elimination by the adaptive immune system [1]
In contrast to the minimal effects of immune checkpoint blockade, we found that a CD40 agonist antibody, FGK4.5, led to a significant reduction in early tumour growth and peritoneal metastatic spread as measured by endpoint imaging of a luciferaseoverexpressing Pan02 tumour cell line (Pan02-cag-luc2; Figure 1D, study outline in Supplementary Figure S1B)
Using a standardised palpation scoring system to measure tumour growth (Supplementary Figure S2), we found that CD40 agonist antibody (αCD40) significantly delayed tumour growth of both wild type Pan02 (Figure 1E) and Pan02-cag-luc2 tumours (Supplementary Figure S3) and delayed the onset of secondary indicators associated with disease progression. αCD40 significantly extended overall survival (Figure 1F), in contrast to αPD-L1 and αCTLA4
Summary
Tumours employ a number of mechanisms to escape detection and elimination by the adaptive immune system [1]. Tumour cells may directly escape T cell surveillance by downregulating expression and presentation of potentially immunogenic tumour-associated antigens [2, 3]. The PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic lymphocyte-associated antigen 4). PD-L1 (programmed death ligand 1) expressed on tumour cells and infiltrating myeloid cells engages PD-1 on activated T cells, downregulating T cell effector functions [5]. CTLA-4 on activated T cells binds to co-stimulatory molecules on antigen presenting cells, inhibiting further T cell activation and expansion, and facilitating suppression by regulatory T cells (Treg) [6]. Antibody therapies blocking PD-1, PDL1 and CTLA-4 function enhance anti-tumour immunity, leading to durable clinical responses for a subset of patients with melanoma, lung cancer and other tumour types [7]. Patients with pancreatic cancer, an aggressive disease with only a 7.2% 5 year survival rate, www.impactjournals.com/oncotarget are reported to respond poorly to checkpoint blockade therapies [8, 9]
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