NOD2 restrains probiotic-mediated TLR2-dependent antitumor immunity

Abstract

The gut microbiota influences cancer immunotherapy, but how interactions among host microbial sensors determine the activity of individual bacteria remains unclear. Here, we show that NOD2 restrains TLR2-dependent antitumor immunity induced by Lactiplantibacillus plantarum. Oral administration of live or heat-killed L. plantarum enhanced immune checkpoint blockade efficacy in mouse tumor models. This activity required host TLR2 signaling and was diminished by disruption of bacterial lipoprotein. In contrast, NOD2 deficiency enhanced tumor control, intratumoral interferon-associated programs, and T cell activation. NOD2 deficiency also amplified chemokine and interferon-associated responses to L. plantarum and the synthetic TLR2 agonist Pam3CSK4 in myeloid cells. Genetic loss or pharmacological inhibition of NOD2 improved Pam3CSK4-mediated tumor control in combination with checkpoint blockade. These findings identify NOD2 as a functional checkpoint on TLR2-driven antitumor immunity and demonstrate that interactions between host microbial-sensing pathways shape the therapeutic activity of commensal bacteria and innate immune agonists.