Sensitizing cancer cells to immune checkpoint inhibitors by microbiota-mediated upregulation of HLA class I
Menée à l'aide de lignées cellulaires et de modèles murins, cette étude démontre que des métabolites libérés par les bactéries, en particulier la phytosphingosine, peuvent augmenter l'expression des antigènes HLA de classe I des cellules cancéreuses et sensibiliser ces dernières aux inhibiteurs de point de contrôle immunitaire
Recent data have shown that gut microbiota has a major impact on the clinical response to immune checkpoint inhibitors (ICIs) in the context of solid tumors. ICI-based therapy acts by unlocking cognate cytotoxic T lymphocyte (CTL) effector responses, and increased sensitivity to ICIs is due to an enhancement of patients? tumor antigen (TA)-specific CTL responses. Cancer clearance by TA-specific CTL requires expression of relevant TAs on cancer cells? HLA class I molecules, and reduced HLA class I expression is a common mechanism used by cancer cells to evade the immune system. Here, we show that metabolites released by bacteria, in particular, phytosphingosine, can upregulate HLA class I expression on cancer cells, sensitizing them to TA-specific CTL lysis in vitro and in vivo, in combination with immunotherapy. This effect is mediated by postbiotic-induced upregulation of NLRC5 in response to upstream MYD88-NF-?B activation, thus significantly controlling tumor growth.