Severe COVID-19 is associated with hyperinflammation and weak T cell responses against SARS-CoV-2. However, the links between those processes remain partially characterized. Moreover, whether and how therapeutically manipulating T cells may benefit patients are unknown. Our genetic and pharmacological evidence demonstrates that the ion channel TMEM176B inhibited inflammasome activation triggered by SARS-CoV-2 and SARS-CoV-2–related murine β-coronavirus. Tmem176b −/− mice infected with murine β-coronavirus developed inflammasome-dependent T cell dysfunction and critical disease, which was controlled by modulating dysfunctional T cells with PD-1 blockers. In critical COVID-19, inflammasome activation correlated with dysfunctional T cells and low monocytic TMEM176B expression, whereas PD-L1 blockade rescued T cell functionality. Here, we mechanistically link T cell dysfunction and inflammation, supporting a cancer immunotherapy to reinforce T cell immunity in critical β-coronavirus disease.

The immunoregulatory cation channel TMEM176B plays a dual role in tumor immunity. On one hand, TMEM176B promotes antigen cross-presentation to CD8+ T cells by regulating phagosomal pH in dendritic cells (DCs). On the other hand, TMEM176B inhibits NLRP3 inflammasome activation through ionic mechanisms in DCs, monocytes and macrophages. Moreover, the TMEM176B blocker BayK8644 controls tumor progression through mechanisms involving inflammasome activation in prophylactic but not in therapeutic protocols. We speculated that the limited therapeutic efficacy of the compound may be linked to its potential capacity to inhibit antigen cross-presentation. Here we show that free BayK8644 inhibits antigen cross-presentation by splenic DCs. To prevent such inhibition, we reasoned that formulating BayK8644 in nanoparticles may delay the release of the compound in endosomes. Avoiding TMEM176B inhibition during the first 30 minutes of nanoparticle internalization by DCs may allow efficient cross-presentation to occur during this critical time frame. Indeed, we observed that NP-PEG-BayK8644 did not inhibit antigen cross-presentation, in contrast to the free compound. Moreover, NP-PEG-BayK8644 triggered inflammasome activation in a Tmem176b-dependent manner. We then injected eNP-PEG or NP-PEG-BayK8644 to mice bearing established tumors. NP-PEG-BayK8644 significantly controlled tumor growth and mice survival, as compared to eNP-PEG and free BayK8644, in a Tmem176b-dependent manner in mouse melanoma and lymphoma tumors. Responding animals treated with NP-PEG-BayK8644 showed reinforced tumor infiltration by total and tumor-specific CD8+ T cells. Overall, we rationally developed a formulating method of BayK8644 that improves its anti-tumoral therapeutic efficacy by uncoupling the dual role of TMEM176B on innate and adaptive immunity.