anti-PD-1 therapy conveys a risk

PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques

Keith D Kauffman, Shunsuke Sakai, Nickiana E Lora, Sivaranjani Namasivayam, Paul J Baker, Olena Kamenyeva, Taylor W Foreman, Christine E Nelson, Deivide Oliveira-de-Souza, Caian L. Vinhaes, Ziv Yaniv, Cecilia S Lindestam Arleham, Alessandro Sette, Gordon J Freeman, Rashida Moore, the NIAID/DIR Tuberculosis Imaging Program, Alan Sher, Katrin D Mayer-Barber, Bruno B Andrade, Juraj Kabat, Laura E Via, Daniel L Barber

 doi: 10.1126/sciimmunol.abf3861,  BioRxiv 

Summary

PD-1 (programmed death-1) is a coinhibitory receptor primarily expressed on activated CD4 and CD8 T cells that has been shown to limit the function of pathogen-specific T cells during chronic infection. The reactive expression of PD-L1 (PD-1 receptor ligand) on cancer cells turns off the T cells that are trying to attack the tumor. Therefore, blockade of PD-1 receptor or its ligands with monoclonal antibodies (mAbs) has become an attractive target in cancer therapy. Recognition of this pathway has led to suggestions that anti–PD-1 therapy might also boost T cell immunity in chronic infections including tuberculosis.

In this recent Science Immunology publication, Kauffman et al. examined the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. It was shown that the PD-1 blockade increased the number and functionality of Mtb-specific CD8 T cells, but not CD4 cells and was associated with increases in proinflammatory cytokines. However, animals treated with anti–PD-1 monoclonal antibody developed worse disease and higher granuloma bacterial loads compared with isotype control–treated monkeys.

These data indicate that negative regulation of immune responses is a critical aspect of host resistance to Mtb infection. Also, these findings suggest that the anti-PD-1 cancer therapy needs to be used cautiously in patients with a history of Mtb exposure.

Results from MultiScan LFER

Mediso MultiScan™ Large Field of view Extreme Resolution (LFER) PET/CT system was used to follow the course of Mycobacterium tuberculosis (Mtb) infection in rhesus macaques. The animals were imaged before infection and every 2 weeks after infection beginning at 4 weeks for a maximum of eight PET-CT scans. [18F] FDG was injected intravenously (1 mCi/kg), and after 60 minutes incubation time a 20-min PET scan was acquired.

(C) Example PET-CT image from isotype control– (top) or PD-1 (bottom)–treated animals. (D) Fold change over week 4 value of total lung standardized uptake value (SUV) in isotype control (left) and PD-1–treated (right) animals.