Oral Presentation Lorne Infection and Immunity 2019

Direct regulation of dendritic cell functions by the immune checkpoint PD-1 (#22)

Christophe Macri 1 , Ee Shan Pang 2 , Jo Pooley 2 , Ben Fancke 3 , Irene Caminschi 2 , Maja Green 4 , Eva Segelov 4 , Mark Shackleton 5 , Daniel Gray 6 , Meredith O'Keeffe 2
  1. Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia
  2. Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
  3. Pathology Division, Peter MacCallum Cancer Centre , Parkville, Victoria, Australia
  4. Monash Health Translation Precinct, Monash University, Clayton, Victoria, Australia
  5. Department of Medicine, Monash University, Melbourne, Victoria, Australia
  6. Molecular Genetics of Cancer Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Blocking anti-PD-1 monoclonal antibodies (mAb) have shown unprecedented success in cancer immune therapies by overcoming activation brakes induced by the immune checkpoint receptor PD-1 expressed on T cells, thus improving anti-tumour T cell immune responses in patients. While immune checkpoint receptors are commonly associated with T cells, we have shown that mouse dendritic cell subsets upregulate PD-1 in response to activation and in the tumour environment. DC lacking PD-1 develop normally and express normal levels of activation markers. However, in the absence of PD-1 or following anti-PD-1 mAb therapies, the cDC1 subset produces higher levels of the cytokine interferon (IFN)-λ, a type III IFN with anti-viral and anti-tumour properties.  Furthermore, PD-1-KO cDC1 are hyperstimulatory towards T cells. In humans, blood DC express PD-1 at variable levels between individuals and PD-1 blocking in cDC1 also increases their capacity to produce IFN-λ, similarly to their mouse counterparts. Altogether, these data show not only T cells, but also DC, are regulated by the immune checkpoint PD-1 and that PD-1 blocking enhances their functions. These findings provide new insights into the mechanism of action of cancer anti-PD-1 immunotherapies and may aid improving their efficacy and their overall safety.