Table 1:

Mechanisms of action that may contribute to microbial effects on immune checkpoint blockade therapy

Proposed Mechanism	Antigen independent/Antigen specific?	Example organism(s) of interest	Phenotypic manifestation(s)	Reference
Autoreactivity of effector T-cells	Antigen Independent Antigen Specific	Campylobacter jejuni, Citrobacter rodentium, Helicobacter hepaticus Gut commensal microbes	Systemic inflammation, Enterocolitis, colorectal cancer (CRC) Activation of retina specific T-cells to cause Uveitis	(31–33)
Activation of TLR signaling pathways	Antigen specific	Engineered Salmonella typhimurium expressing FlaB from Vibrio vulnificus	Tumor suppression in CRC mouse model in a TLR4 and TLR5 dependent manner	(34)
Genetic variants	Antigen independent	Varies	Protein tyrosine phosphate non-receptor type22 (PTPN22) variant prevents select autoimmunity and shapes microbial composition	(25)
Molecular Antigen Mimicry	Antigen specific	Bacteroides fragilis; Fusobacterium spp., Leptotrichia goodfellowii Gut commensal microbes	Activation of protein MyD88 leads to Type I diabetes in NOD mice Progression to inflammatory myocarditis driven by microbial peptide stimulated Th17 cells	(26, 27, 35)
Bacterial translocation from the gut	Antigen independent	Enteroccocus gallinarum	Systemic lupus erythematosus (SLE), chronic autoimmunity	(36)

Select studies highlighting potential drivers of external immune stimulation and autoimmunity in humans and mice that may be implicated or exacerbated in the context of immune checkpoint blockade.