Checkpoint inhibitors, anti-PD1/anti-PD-L1 activities are channeled via CD28 co-stimulation

Two new back-to-back studies in Science showed that T cell recovery activity attributed to checkpoint inhibitors, anti-PD1/anti-PD-L1, is mediated via CD28 co-stimulation. One of the study focused on analysis of biochemical events leading to PD1 signaling in an in vitro reconstitution model and another study provided corroborating data using mouse model. 

Summary results from both studies suggest that anti-PD1/PD-L1 activity is lost when T cells lack co-stimulatory molecule CD28. However, readouts here are more complicated since PD-L1 itself could bind to CD28 ligand B7 molecule. Also, I noticed that by default T cells with inducible CD28 deficiency (CD28^f/f Cre^ERT2+) show less accumulation and/or survival (low cell density) compared to WT counterparts.

Another confusion has to do with the fact that at least in one of the clinical trials anti-CD28 antibodies produced severe cytokine release syndrome and program was discontinued. It could be that anti-PD1/PDL1 therapy activates only certain type of T cells while anti-CD28 could have targeted much larger T cell population.

David Usharauli

  

cGAS puts gas on anti-tumor effect of checkpoint inhibitor

This week PNAS published new article explaining mechanism of action of checkpoint inhibitors, such as anti-PDL1, in tumor immunity. It shows that cytoplasmic DNA sensor cGAS/STING pathway synergize with anti-PDL1 therapy in mouse model of melanoma.

While this study provides noteworthy observation, it is poorly done. For example, when comparing WT and KO mice (cGAS or STING KO mice), the authors did not mention if they used littermate control in these experiments.

In addition, when the authors used exogenous cGAMP (product of cGAS activity detected by STING), they did not use it on cGAS or STING KO mice as controls to verify relationship between cause and effect.   

    

In summary, the connection between DNA recognition system and checkpoint inhibitors is very interesting. Whether it is a simple generic augmentation of T cell priming or specific stimulation of tumor-specific T cells is to be seen.   

David Usharauli

Gut commensal Bifidobacterium promotes anti-cancer efficacy of anti-PD-L1 immunotherapy. Part II

This is a second paper in this series (microbiota and immunotherapy). This study came from Thomas Gajewski's lab. It showed that cancer growth or effectiveness of anti-PD-L1 anti-cancer immunotherapy were influenced by composition of gut microflora, more specifically by presence of Bifidobacterium. 

Now this paper starts with experimental results that became classical experiments in gut immunology [since the discovery of TH17 subset]. Namely, the authors showed that B6 black mouse colonies derived from JAX lab or Taconic showed different susceptibility to cancer growth.

This difference between JAX and Taconic mice disappeared when mice were co-housed, implying the role of gut microflora. 

This hypothesis was confirmed in fecal cross-feeding experiments between JAX and Tac mice. It turned out that gut microbiota from JAX mice could enhance anti-tumor immunity when transplanted into Tac mice [but not vise versa].

Furthermore, JAX mouse microbiota could enhance anti-cancer effectiveness of anti-PD-L1 immunotherapy.

Finally, the authors found that a single commensal species, called Bifidobacterium, was largely responsible for microbiota's effect on cancer immunity.

In summary, the authors proposed that live Bifidobacterium could enhance anti-cancer immunity by supporting "generic" dendritic cell maturation and improving T cells antigen-sensitivity. 

This model, however, lacks data that could meaningfully explain why and how only Bifidobacterium has such influence on anti-cancer immunity. Also, it would have been more relevant to test FDA approved anti-PD1 antibody here rather than not-yet-approved anti-PD-L1 antibody therapy. 

David Usharauli