Tumor cell lysates as immunogenic sources for cancer vaccine design

Abstract

Autologous dendritic cells (DCs) loaded with tumor-associated antigens (TAAs) are a promising immunological tool for cancer therapy. These stimulate the antitumor response and immunological memory generation. Nevertheless, many patients remain refractory to DC approaches. Antigen (Ag) delivery to DCs is relevant to vaccine success, and antigen peptides, tumor-associated proteins, tumor cells, autologous tumor lysates, and tumor-derived mRNA have been tested as Ag sources. Recently, DCs loaded with allogeneic tumor cell lysates were used to induce a potent immunological response. This strategy provides a reproducible pool of almost all potential Ags suitable for patient use, independent of MHC haplotypes or autologous tumor tissue availability. However, optimizing autologous tumor cell lysate preparation is crucial to enhancing efficacy. This review considers the role of cancer cell-derived lysates as a relevant source of antigens and as an activating factor for ex vivo therapeutic DCs capable of responding to neoplastic cells. These promising therapies are associated with the prolonged survival of advanced cancer patients.

Keywords: AM, Cytokine-activated monocytes; Ags, Antigens; CDAMs, Cell death-associated molecules; CRT, Calreticulin; CTLs, Cytotoxic T lymphocytes; DAMPs; DAMPs, Damage-associated molecular patterns; DCs, Dendritic cells; DTH, Delayed-type IV hypersensitivity; GM-CSF, Granulocyte and macrophage colony stimulating factor; HMGB1, High-mobility group box 1 protein; HSPs, Heat shock proteins; ICD, Immunogenic cell death; MAAs, Melanoma-associated antigens; MHC, Major histocompatibility complex; MM, Malignant melanoma; NKT, Natural killer T cell; PAMPs, Pathogen-associated molecular patterns; PBMCs, Peripheral blood mononuclear cells; PCCL, Prostate cancer cell lysate; PD1, Programmed cell death protein 1; PRRs, Pattern recognition receptors; PSA, Prostate specific antigen; RAGE, Receptor for advanced glycation endproducts; SNPs, Single nucleotide polymorphisms; TAAs, Tumor-associated antigens; TAPCells, Tumor antigen presenting cells; TCRs, T cell receptors; TLRs, Toll-like receptors; TNF, Tumor necrosis factor; TRIMEL, Allogeneic melanoma cell lysate; TRIPRO, Allogeneic prostate cell lysate; Toll-like receptors; Tregs, Regulatory T lymphocytes; cancer immunotherapy; dendritic cells; immunogenic cell death.

Figure 1.

Summary of the effects of stressed cancer cell-derived lysates on the phenotypic and functional characteristics of ex vivo-generated DCs. The ex vivo stimulation of therapeutic TAPCells with 2 different cancer cell-derived lysates (TRIMEL and TRIPRO) induced rapid (24–48 hours) and committed maturation to Th1/Th17 polarizing DCs. This is achieved through the engagement of different cancer cell-expressed DAMPs (e.g. CRT and HMGB1), and by induction through a previous heat conditioning of cancer cells, with different innate immune-receptors (e.g., TLR2, TLR4, and RAGE) expressed on the surface of AM (an immature DC phenotype). These functional characteristics include the secretion of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), the migration capacity to draining lymph nodes, Th1 and Th17 polarizing cytokines (IL-12, IFN-α, and IL-17) and the presentation and cross-presentation of TAAs to naïve CD4⁺ and CD8⁺ T lymphocytes, respectively, which can explain, at least in part, the in vivo responses observed in vaccinated MM and prostate cancer patients.