Immunogenic Cell Death and Role of Nanomaterials Serving as Therapeutic Vaccine for Personalized Cancer Immunotherapy

Abstract

Immunogenic cell death (ICD) is a rapidly growing research area representing one of the emerging therapeutic strategies of cancer immunotherapy. ICD is an umbrella term covering several cell death modalities including apoptosis, necroptosis, ferroptosis and pyroptosis, and is the product of a balanced combination of adjuvanticity (damage-associated molecular patterns and chemokines/cytokines) and antigenicity (tumor associated antigens). Only a limited number of anti-cancer therapies are available to induce ICD in experimental cancer therapies and even much less is available for clinical use. To overcome this limitation, nanomaterials can be used to increase the immunogenicity of cancer cells killed by anti-cancer therapy, which in themselves are not necessarily immunogenic. In this review, we outline the current state of knowledge of ICD modalities and discuss achievements in using nanomaterials to increase the immunogenicity of dying cancer cells. The emerging trends in modulating the immunogenicity of dying cancer cells in experimental and translational cancer therapies and the challenges facing them are described. In conclusion, nanomaterials are expected to drive further progress in their use to increase efficacy of anti-cancer therapy based on ICD induction and in the future, it is necessary to validate these strategies in clinical settings, which will be a challenging research area.

Keywords: antitumor therapy; ferroptosis apoptosis; immunogenic cell death; immunogenicity; nanomaterials; necroptosis; pyroptosis.

Figure 1

An overview of drug delivery carriers used to modulate immunogenic cell death modalities. To modulate the immunogenicity of cell death, drug delivery carriers can be used at three different levels: (1) cell death and (2) modulation of the dying cell’s uptake.

Figure 2

Overview of the specific ICD mediators for each cell death type. Apoptosis (7, 53, 54), Necroptosis (10, 53, 55, 56), Pyroptosis (, –60); Ferroptosis (12) and; Damage-associated molecular patterns (DAMPs); Calreticulin (CRT); high mobility group box-1 (HMGB-1); interleukin (IL); chemokine (C-X-C motif) ligand (CXCL).

Figure 3

(A) An overview of the molecular mechanisms of ICD modalities and the in vivo models to assess it. ICD results as a balanced combination of adjuvanticity (induced by DAMPs and chemokines/cytokines) and antigenicity (tumour-associated antigens), which together promote the recruitment of antigen-presenting cells (APCs) and stimulate their ability to take up particulate material and cross-present dead cell-associated antigens to CD4⁺ and CD8⁺ cytotoxic T lymphocytes (Box 1). (B, C) represent the two recognized models to assess ICD in vivo. (B) In a tumour prophylactic vaccination model, cancer cells are first induced in vitro to undergo a particular form of ICD (apoptosis, necroptosis, pyroptosis or ferroptosis). They are then inoculated subcutaneously on one flank of the mice. Eight days later, the mice are challenged subcutaneously on the opposite flank with live cancer cells. Tumour growth at the challenge site is monitored. (C) In the bilateral tumour model, only the primary tumour is treated with the ICD inducers. The ability of mice to reject or limit the growth of primary and distant tumours is considered a sign of protective anticancer immunity.

Figure 4

Dawn of immunotherapy spurred by immunogenic cell death (ICD) and enables by drug delivery carriers. Strategies to increase ICD and its requirements, the left column, are to be met by capabilities in the area of drug delivery carriers, the right column. This truly represents a dawn of a new era linked to immunotherapy (and this message is conveyed in the background).