Engineered tumor cell-derived vaccines against cancer: The art of combating poison with poison

Abstract

Tumor vaccination is a promising approach for tumor immunotherapy because it presents high specificity and few side effects. However, tumor vaccines that contain only a single tumor antigen can allow immune system evasion by tumor variants. Tumor antigens are complex and heterogeneous, and identifying a single antigen that is uniformly expressed by tumor cells is challenging. Whole tumor cells can produce comprehensive antigens that trigger extensive tumor-specific immune responses. Therefore, tumor cells are an ideal source of antigens for tumor vaccines. A better understanding of tumor cell-derived vaccines and their characteristics, along with the development of new technologies for antigen delivery, can help improve vaccine design. In this review, we summarize the recent advances in tumor cell-derived vaccines in cancer immunotherapy and highlight the different types of engineered approaches, mechanisms, administration methods, and future perspectives. We discuss tumor cell-derived vaccines, including whole tumor cell components, extracellular vesicles, and cell membrane-encapsulated nanoparticles. Tumor cell-derived vaccines contain multiple tumor antigens and can induce extensive and potent tumor immune responses. However, they should be engineered to overcome limitations such as insufficient immunogenicity and weak targeting. The genetic and chemical engineering of tumor cell-derived vaccines can greatly enhance their targeting, intelligence, and functionality, thereby realizing stronger tumor immunotherapy effects. Further advances in materials science, biomedicine, and oncology can facilitate the clinical translation of tumor cell-derived vaccines.

Keywords: Biomaterials; Cancer; Engineering; Immunogenicity; Immunotherapy; Nanotechnology; Vaccine.

Graphical abstract

Scheme 1

Illustration of novel strategies for engineered tumor cell-derived vaccines. The cellular components used as tumor cell-derived vaccines include tumor whole cell fractions, extracellular vesicles, and cell membrane-coated nanoparticles. Three main engineering strategies (comprising genetic engineering, surface engineering, and internal cargo loading) are used to enhance the therapeutic efficacy of tumor vaccines. The antitumor mechanisms of tumor cell-derived vaccines include: 1) direct killing of tumor cells through surface-specific receptor targeting, the release of cytokines at the tumor site, or drug-induced tumor immunogenic cell death (ICD); 2) targeting dendritic cells (DCs) by delivering large amounts of antigen; the mature DCs then present the antigen as an antigenic peptide on the cell surface and secrete a variety of cytokines to induce T cell activation and kill the tumor; and 3) remodeling the tumor microenvironment (TME) by eliciting local inflammation, polarization of macrophages, natural killer cell (NK) recruitment, etc. (Created with BioRender.com).

Fig. 1

Whole tumor cell vaccine. (A) Therapeutic effects of knockout Id2 mouse neuroblastoma cells (Id2kd-N2a) as a vaccine in combination with checkpoint inhibitors α-PD-L1 and α-CTLA-4 in tumor-bearing mice. (B) Tumor imaging in mice after α-PD-L1+α-CTLA-4+Id2kd N2a treatment. Copyright © 2018 Srinivasan et al. [89] (C) Schematic illustration of the design of walking dead triple-negative breast cancer cells for suppressing lung metastasis with temporal chemoimmunotherapy. (D) After intravenous injection of 4T1-tumor-bearing mice, cell-PD-1/Liposomes (DiR-labeled) accumulated in major organs over time. (E) Inhibitory effect on subcutaneous 4T1 tumor mouse model. Copyright © 2022 Wiley-VCH GmbH [90].

Fig. 2

Tumor lysate vaccines delivered by carriers for cancer immunotherapy. (A) The preparation of nanovaccines and the tumor-specific immune responses induced by nanovaccines. Copyright © 2021, Wiley–VCH GmbH [21]. (B) Polydopamine nanoparticles loaded with whole tumor cell lysates (TCL@PDA) as a therapeutic vaccine for colorectal cancer. (C) Anticancer preventive effect of TCL@PDA in vivo at day 20. Copyright © The Royal Society of Chemistry 2019 [105]. (D) The PLEL-based combination strategy to amplify cancer immunotherapy. Copyright © 2021 Yang et al. [111].

Fig. 3

Exosomes with internal cargo as therapeutic tumor vaccines. (A) Antitumor immune responses induced by C-PMet-based immunometabolic therapy. (B) Therapeutic effect of inhibiting lung metastasis of tumors. Copyright © 2022 Wu et al. [150]. (C) The preparation of Au@MC38 and in vivo radiosensitization for cancer therapy. (D) In vivo homologous targeting and in vitro transcytosis. Copyright © 2021, Wiley–VCH GmbH [151].

Fig. 4

Cancer cell membranes combined with immune adjuvants as a nanovaccine for cancer immunotherapy. (A) Preparation of a DC-targeted tumor vaccine with cholesterol-modified CpG and cholesterol-modified DC-SIGN aptamer inserted on the surface of the tumor cell membrane (CMV-CpG/Apt). (B) The therapeutic effect of CMV-CpG/Apt in B16-OVA tumor-bearing mice. Copyright © 2021, American Chemical Society [179]. (C–D) Therapeutic efficacy of a tumor cell membrane vaccine with surface modifications of glycolipid-anchored immune stimulatory molecules GPI-B7-1 and GPI-IL-12 combined with anti-PD-1 mAb, inhibiting MOC1 tumor growth (C) and MOC2 tumor growth (D). Copyright © 2020 Bommireddy et al. [180]. (E) Cancer therapy with lipocomplexes (Lp-KR-CCM-A). When laser irradiated, Lp-KR-CCM-A produces reactive oxygen species and kills cancer cells [184]. Copyright © 2019, American Chemical Society.

Fig. 5

Hybrid cell membrane nanovaccines based on DCs and tumor cells for cancer immunotherapy. (A) Schematic of fused cells membrane-coated PCN-224 (PCN@FM) for combined tumor therapy and (B) evaluation of homotypic targeting, immune activation, and PDT efficacy in vitro [33]. Copyright © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (C) Schematic of fused cells membrane-coated PCN-224 nanoparticles (NP@FM) for tumor prevention and the mechanisms by which NP@FM induces immune responses. (D) The effect of fused cells membrane-coated PCN-224 MOF (MOF@FM) as a preventive vaccine against tumor suppression [201]. Copyright © 2019, Liu et al.

Fig. 6

Fusion of bacterial outer membranes/tumor cell membrane-based nanovaccines for immunotherapy. (A) The fabrication of eukaryotic-prokaryotic vesicle-coated PI@EPV nanovaccines. (B) Fusion membrane vesicle endocytosis by DC2.4 murine dendritic cells (C) Tumor growth curves in a melanoma breast cancer model after immunization with the nanovaccine. (D) Percentage of tumor-free mice after tumor challenge. (E–F) The proportions of splenic lymphocytes expressing different T cells after immunization. Copyright © 2020, WILEY–VCH Verlag GmbH & Co. KGaA, Weinheim [125].

Fig. 7

Therapeutic strategies of engineered tumor cell-derived vaccines. These strategies include the delivery of adjuvants, chemotherapy drugs, photosensitizers, radioactive molecules, antigens, MHC molecules, and immunomodulatory molecules, which can activate the immune system and reverse the suppressive tumor microenvironment.

Fig. 8

Summary of tumor-derived nanovaccines. Tumor tissue/cells removed from the patient or cultured in the laboratory can be extracted to obtain the desired tumor cell components. After engineered modifications, they can deliver a variety of active substances to the tumor originator and exert antitumor effects through different strategies. In the future, we will need to pay attention to standardized quality specifications during production to ensure a pure, safe, and economically viable vaccine, which is a challenge (Created with BioRender.com).