An Injectable Hydrogel to Modulate T Cells for Cancer Immunotherapy

Abstract

T cell exhaustion caused by mitochondrial dysfunction is the major obstacle of T cells‐based cancer immunotherapy. Besides exhausted T cells, the insufficient major histocompatibility complex class I (MHC I) on tumor cells leads to inefficient T cell recognition of tumor cells, compromising therapeutic efficacy. Therapeutic platform to regulate T cell exhaustion and MHC I expression for boosting T cells‐based cancer immunotherapy has not been realized up to date. Herein, an injectable hydrogel is designed to simultaneously tune T cell exhaustion and MHC I expression for amplified cancer immunotherapy. The hydrogel is in situ constructed in tumor site by utilizing oxidized sodium alginate‐modified tumor cell membrane vesicle (O‐TMV) as a gelator, where axitinib is encapsulated in the lipid bilayer of O‐TMV while 4‐1BB antibody and proprotein convertase subtilisin/kexin type 9 inhibitor PF‐06446846 nanoparticles are present in the cavities of hydrogel. After immune response trigged by O‐TMV antigen, the 4‐1BB antibody‐promoted T cell mitochondrial biogenesis and the axitinib‐lowered hypoxia synergistically reverse T cell exhaustion while the PF‐06446846‐amplified MHC I expression facilitates T cell recognition of tumor cells, demonstrating a powerful immunotherapeutic efficacy. This strategy on reprograming T cell exhaustion and improving T cell potency offers new concept for T cells‐based cancer immunotherapy.

Hydrogel systems for targeted cancer therapy

“…The hydrogel can be loaded with multiple types of immune checkpoint blockers and chemicals that can increase cancer immunogenicity and enhance cytotoxic T lymphocyte infiltration. The hydrogel also allows for the sustained release of these drugs in a sequence that not only induces a cascade of immune responses for synergistic therapeutic benefits, but also reduces drug resistance and the number of injections ( Zhang et al, 2022a ; Passaro et al, 2022 ). In addition, the encapsulation of the hydrogel enhances the penetration of immunotherapeutic agents to a certain extent and facilitates the long-term accumulation of drugs ( Li et al, 2021 ).…”

A Three‐in‐One Nanoscale Coordination Polymer for Potent Chemo‐Immunotherapy

“…[43,44] As peripheral blood mononuclear cell (PBMCs) have been reported to reflect the behaviors of tumorinfiltrating T cells, [45] they were used as surrogates for T cells in in vitro studies. [46] We assessed the influence of CQ-NCPmediated PD-L1 downregulation on T cell function by apoptosis assays of CQ-NCP-treated MC38 cells with or without co-incubation of PBMCs (Figure 3c,d). CQ-NCP treatment only caused 3.57 ± 0.57% cell death, but the addition of PBMCs significantly increased the apoptosis percentage to 22.35 ± 2.97%, suggesting that CQ-NCP enhanced the activity of PBMCs via PD-L1 downregulation.…”

Hydrogel‐Based Strategies to Enhance T‐Cell Performance for Solid Tumor Immunotherapy

“…Indeed, axitinib helped supply oxygen into the TME for recovery of mitochondrial function. [84] Reactive oxygen species (ROS) are known to cause aging or cancer in normal tissues, and interestingly also increase in hypoxia. [121] Although ROS has beneficial properties such as polarization of macrophages to pro-inflammatory phenotype, it has dual effects [135] in turning tumor microenvironments to be more immunosuppressive.…”

“…[154] As mentioned previously, Zhang et al encapsulated multiple chemotherapeutic drugs in nanoparticles within O-TMV, such as 4-1BB antibody, a T cell activating agent, and PCSK9 inhibitor, an anti-cancer drug, to enhance T cell viability and reversion from exhaustion. [84] In vitro and in vivo experiments revealed that the hydrogel scaffold effectively reversed T cell exhaustion through promotion of mitochondrial biogenesis through alleviated hypoxia and increased T cell proliferation, and triggered improved recognition of cancer cells by T cells. This study is especially valuable as the immunosuppressive TME can easily exhaust T cells that make it to the tumor site, and rejuvenation of T cells in tumor tissues is especially important in solid tumors for successful therapy.…”