Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• STING

• Central Memory

• Monocytes/Macrophages

Main Findings

The cGAS/STING pathway has been shown to be a power adjuvant for tumor immunity in preclinical trials and many therapeutic strategies have been aimed to target this pathway to elicit potent tumor immune control. In this paper, the authors found that STING agonists are potent immune adjuvants that induce robust antigen-specific CD8 T cell response in an OT-I vaccination model. This model uses adoptive transfer of T cells from the OT-1 T-cell receptor transgenic mouse followed by vaccination with peptide, allowing for expansion and tracking of OVA-specific CD8 T cells by flow cytometry. When comparing adjuvanticity of STING agonists DMXAA and clinically relevant ADU-S100 to CD40 agonism, the authors found that targeting STING elicits less PD1 expression on T cells and more rapid conversion to a central memory-dominated antigen specific response that was intrinsic to treatment with STING agonists. Interestingly, they found that this was dependent upon STING signalling and macrophages and monocytes, in addition to type I IFN and TNFa, with broader implications for understanding effective anti-tumor immunity.

Limitations

(1) Vaccination model with a very potent antigen may not be representative of response to tumor antigens

(2) Some data inconsistencies between studies in the paper:

• Differences in magnitude of primary antigen specific CD8 response with DMXAA (or a lack of dosing information)

• Dependence on aCSF1/CSF1R for initial antigen specific response, but aCCR2/aCSF1 for control of long-term memory conversion

(3) DMXAA and ADU-S100 secondary challenge responses undercharacterized

(4) Myeloid-CD8 T cell crosstalk undercharacterized (most interesting)

• Study of ligand-receptor interactions that lead to myeloid-dependent conversion of memory responses is lacking

(5) Lack of CD4 characterization (study of OT-II would be helpful)

(6) Inconsistencies in conclusions – the authors implicated rapid central memory conversion as being critical for anti-tumor response (intrinsic to STING agonism), but ADU-S100 performed the same as CD40 in the Figure 6 in terms of survival, suggesting this may not be the main driver of anti-tumor immunity or that the pharmacokinetics differ from vaccination model.

Significance/Novelty

Myeloid-dependence of both initial antigen-specific CD8 T cell responses and rapid memory conversion intrinsic to STING agonism is pretty novel – ligand-receptor interactions or metabolites responsible for these interactions could yield new clinical targets to bolster anti-tumor immunity.

Potential implications for outcome measures of future STING agonism preclinical trials studying longer-term CD8 memory responses and targeting of myeloid cells specifically, though main findings were somewhat inconsistent with tumor data in the final figure.

Credit

Reviewed by Natalie Vaninov as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.