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. 2023 Oct 9;41(10):1717-1730.e4.
doi: 10.1016/j.ccell.2023.08.014. Epub 2023 Sep 21.

Sensitizing cancer cells to immune checkpoint inhibitors by microbiota-mediated upregulation of HLA class I

Valentina Ferrari  1 , Antonino Lo Cascio  2 , Alessia Melacarne  2 , Nina Tanasković  3 , Alessandro M Mozzarelli  4 , Luca Tiraboschi  2 , Michela Lizier  2 , Marta Salvi  4 , Daniele Braga  2 , Francesca Algieri  3 , Giuseppe Penna  5 , Maria Rescigno  6
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Free article

Sensitizing cancer cells to immune checkpoint inhibitors by microbiota-mediated upregulation of HLA class I

Valentina Ferrari et al. Cancer Cell. .
Free article

Abstract

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-κB activation, thus significantly controlling tumor growth.

Keywords: anti-PD-1; cancer; immunotherapy; microbiota; tumor-specific T cells.

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Conflict of interest statement

Declaration of interests M.R. is co-founder and CSO of Postbiotica S.r.l, consultant for Millbo and research collaborator for Gelesis and Alfa Sigma. G.P. is co-founder and scientific advisor of Postbiotica S.r.l. F.A. and N.T. are employees of Postbiotica S.r.l.

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