Ultrasound has demonstrated versatility in cancer immunotherapy. However, insufficient co-stimulating molecules and loss of peptide-major histocompatibility complex I (MHC-I) expression on tumor cells lead to poor therapeutic effect. Additionally, concurrent enhancement of both T cells and Natural killer (NK) cells through ultrasound strategy remains underexplored. 

In a study published in Advanced Materials, a research team led by LI Yaping from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences (CAS), along with collaborators, constructed a sonosensitive system named dead APC-4T1-N3-LipoH (DPNL) using reprogrammed antigen-presenting cells (APC)-like tumor cells. Upon ultrasound irradiation, DPNL cells could co-stimulate antigen-presenting program, effectively triggering  antigen-specific T cell-mediated adaptive immunity in tumor draining lymph nodes (TDLNs) and MHC-I unrestricted NK cell-mediated innate immunity within tumors, enabling comprehensive sonoimmunotherapy for solid tumors.

These cryo-shocked sonosensitive APC-like tumor cells, named DPNL, were reprogrammed from tumor cells using Cebp and Pu.1 transcription regulators. They featured sufficient co-stimulating molecules (MHC-I, CD40, CD80, CD86) and homologous targeting molecules (CCR5, E-cadherin). Subsequently, they were cryo-shocked and conjugated with clinically approved sonosensitizer hematoporphyrin monomethyl ether (HMME) via click chemistry. In this sonosensitizer delivery system, the homologous targeting features of both APC (CCR5) and tumor cells (E-cadherin) enabled dual targeting of tumor immune microenvironment (TIME) and TDLN. Upon ultrasound irradiation, spatial and temporal controllable immunogenic cell death and DNA damage response were triggered in tumor cells, activating NK cell-mediated innate immunity via MHC-I unrestricted Nature killer group 2 D-Nature killer group 2 D ligand (NKG2D-NKG2DL) pathway. Meanwhile, the co-stimulating molecules (CD80, CD86) on DPNL improved T cell-mediated adaptive immunity in TDLNs. This dual activation of NK cell-based innate immunity and T cell-based adaptive immunity resulted in suppressed tumor growth, decreased lung metastasis and prolonged survival time of solid tumors-bearing mice.

The constructed sonosensitive, cryo-shocked, reprogrammed tumor cells exhibit dual homologous targeting features of both APC and tumor cells, along with co-stimulating molecules (CD80, CD86). These cells can serve as spatiotemporal sonosensitizer delivery cargoes and initiators for amplifying NK cell-based innate immunity and T cell-based adaptive immunity. 

This study utilized and elucidated role of ultrasound and co-stimulating molecules in antigen-presenting process, specifically by triggering MHC-I unrestricted NKG2D-NKG2DL pathway in TIME and binding to co-stimulating receptors on T cells in TDLNs. Reprogramming cancer cells into APC-like subsets and conjugating them with clinically approved sonosensitizer HMME via click chemistry represents a clinically accessible and efficient sonosensitizer delivery strategy, which provided a new insight into spatiotemporal modulation of immune response and potentially advance cancer sonoimmunotherapy.

DOI: 10.1002/adma.202413289. 

Link: https://doi.org/10.1002/adma.202413289 

Schematic of DPNL synergizing with SDT and anti-PD-L1 checkpoint blockade to augment sonoimmunotherapy via T cell-based adaptive immunity and NK cell-mediated innate immunity. (Image by Prof. LI’s lab)

Contact:

JIANG Qingling

Shanghai Institute of Materia Medica, Chinese Academy of Sciences

E-mail: qljiang@stimes.cn