Combined dendritic cell and anti-TIGIT immunotherapy potentiates adaptive NK cells against HIV-1

Abstract

Dendritic cell; HIV; Natural killer

Cèl·lula dendrítica; VIH; Assassí natural

Célula dendrítica; VIH; Asesino natural

Natural Killer (NK) cells are promising candidates for targeting persistently infected CD4 + T cells in people with HIV-1 (PWH). However, chronicity of HIV-1 infection impairs NK cell functionality, requiring additional strategies to potentiate their cytotoxic activity. This study demonstrates that dendritic cells primed with nanoparticles containing Poly I:C (Nano-PIC-MDDC) enhance the natural cytotoxic function of NK cells from effective responder PWH. These NK cells exhibit increased proportions of NKG2C+ cell subsets capable of eliminating HIV-1 infected CD4 + T cells through the TRAIL receptor. In contrast, in non-responder PWH, elevated expression of the inhibitory receptor TIGIT is associated with reduced frequencies of NKG2C + NK cells and diminished TRAIL expression. TIGIT blockade restores cytotoxicity of NK cells from non-responder PWH against HIV-1-infected cells by upregulating TRAIL. Furthermore, combining Nano-PIC-MDDC-primed NK cells with anti-TIGIT immunotherapy in humanized NSG mice reduces the expansion of HIV-1 infected cells, preserves NKG2C + NK cell precursors and increases TRAIL expression in tissue. Collectively, these findings support the combined use of Nano-PIC-MDDC and TIGIT blockade as a promising immunotherapeutic strategy toward an HIV-1 cure.

EMG was supported by Ramón y Cajal Program (RYC2018-024374-I), the Spanish Agencia Estatal de Investigación RETOS, Generación de conocimiento and consolidation programs (RTI2018-097485-A-I00; PID2021-127899OB-I00; CNS2023-144841), La Caixa Banking Foundation ETI-CureHIV (HR20-00218), GLD24/00117 grant from Gilead Biosciences and infectious diseases CIBER (CIBERINFEC) from ISCIII (CB21/13/00107). MAL was supported by the Formación de Personal Investigador (FPI) grant PRE2022-104516. IT was supported by FPI UAM fellowship. CDA was supported by Comunidad de Madrid Talento Program (2017-T1/BMD-5396). MCM was supported by La Caixa Foundation ETI-CureHIV (HR20-00218). P2022/BMD7209-INTEGRAMUNE from Comunidad Autónoma de Madrid and La Caixa Health Research Grant LCF/PR/HR23/52430018 to and PID2023-149541OB-I00 FSM also supported the study. ISC was supported by infectious diseases CIBER from ISCIII (CB21/13/00107). JGP was supported by La Caixa Health program ETI-CureHIV project (HR20-00218), the CIBERINFECC from the National Health Institute Carlos III, and the project PI22/01120. MLT was supported by the Spanish Agencia Estatal de Investigación, Ministerio de Ciencia, Innovación y Universidades (PID2022-138880OB-I00 and PDC2021-121238-I00). NMC contributed to ROC Curve analysis.