Abstract 1684: Selective SIRPa blockade potentiates dendritic cell antigen cross-presentation and triggers memory T-cell antitumor responses
Authors: Gauttier Vanessa , Pengam Sabrina , Durand Justine , Morello Aurore , Conchon Sophie , Vanhove Bernard , Poirier Nicolas 
Published: August 2018

Targeting immune checkpoints of the adaptive immunity has shown great therapeutic efficacy to fight cancers, but in a limited proportion of patients. Myeloid cells represent a major immune cell type in many solid tumors, and are often associated with a poor outcome. Interaction of SIRPalpha (SIRPa), expressed by myeloid cells, with the ubiquitous receptor CD47 is an important immune checkpoint of the innate response, involved in the regulation of macrophages and neutrophils functions including phagocytosis. Targeting both adaptive and innate immune cells represents a promising therapeutic strategy against cancer. Here we evaluated the impact of a SIRPa checkpoint inhibitor on adaptive immune responses both in rodents and human settings.

Antagonist anti-SIRPa monoclonal antibody (mAbs) was evaluated in vivo in combination with adaptive immune checkpoint inhibitors (anti-PD-L1 mAb) or costimulatory agent (anti-4-1BB mAb) in an orthotopic hepatocellular carcinoma (HCC) model in immunocompetent mice. Whereas monotherapies have shown a modest clinical effect, combination with SIRPa blockade dramatically enhanced the overall survival with up to 70% of mice in complete remission (p &lt; 0.0001 in both combination: n=15 with anti-41BB and n=11 with anti-PDL1 combination). These cured mice showed robust memory immune response since a second tumor challenge (performed up to one month after treatment withdrawal) was rejected in all mice (p&lt;0.01 n=20). In addition, adaptive transfer of T lymphocytes from 4-1BB combo or sera from PD-L1 combo cured mice in naïve untreated mice protected them from orthotopic HCC development (n=5/6 with T-cell from 4-1BB combo; n=5/5 with sera from PD-L1 combo). Tumor infiltrates analyzed by flow cytometry showed enrichment in effector CD8 T cells with the 4-1BB therapy whereas PD-L1 combination led to an accumulation of memory CD4 T cells. Tumor transcriptional analysis using Nanostring technology revealed higher dendritic cells (DCs) and T cells (mainly TH1) immune signature with reduced exhaustion signature. Finally, we found in vitro that selective blockade of SIRPa during antigen processing by mouse dendritic cells (with ovalbumin protein and TCR-transgenic OT-1 T-cell) or human dendritic cells (with melan-A 25-mer long peptide and human antigen-specific T-cell clone from melanoma patients) significantly increases T-cell activation and cytokine (i.e. IFNg) secretion.

In conclusion, we showed that selective SIRPa antagonist increased dendritic cell tumor-antigen cross-presentation and generated robust antitumor memory response in combination with adaptive immunotherapies.

Citation Format: Vanessa Gauttier, Sabrina Pengam, Justine Durand, Aurore Morello, Sophie Conchon, Bernard Vanhove, Nicolas Poirier. Selective SIRPa blockade potentiates dendritic cell antigen cross-presentation and triggers memory T-cell antitumor responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1684.