title: Transformation of the tumour microenvironment by a CD40 agonist antibody correlates with improved responses to PD-L1 blockade in a mouse orthotopic pancreatic tumour model.
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.
authors.affiliation: MedImmune Ltd., Cambridge CB21 6GH, UK.
authors.forename: Nadia M
authors.initials: NM
authors.lastname: Luheshi
authors.affiliation: MedImmune Ltd., Cambridge CB21 6GH, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Coates-Ulrichsen
authors.affiliation: MedImmune Ltd., Cambridge CB21 6GH, UK.
authors.forename: James
authors.initials: J
authors.lastname: Harper
authors.affiliation: MedImmune Ltd., Cambridge CB21 6GH, UK.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mullins
authors.affiliation: MedImmune Ltd., Cambridge CB21 6GH, UK.
authors.forename: Michal G
authors.initials: MG
authors.lastname: Sulikowski
authors.affiliation: MedImmune LLC., Gaithersburg, MD 20878, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Martin
authors.affiliation: MedImmune Ltd., Cambridge CB21 6GH, UK.
authors.forename: Lee
authors.initials: L
authors.lastname: Brown
authors.affiliation: MedImmune Ltd., Cambridge CB21 6GH, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Lewis
authors.affiliation: MedImmune Ltd., Cambridge CB21 6GH, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Davies
authors.affiliation: MedImmune Ltd., Cambridge CB21 6GH, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Morrow
authors.affiliation: MedImmune Ltd., Cambridge CB21 6GH, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D019013:CD40 Antigens / Q000819:agonists* / Q000276:immunology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D011897:Random Allocation; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; C556707:Ctla4 protein, mouse
keywords: CD40; PD-L1; microenvironment; pancreatic cancer