Photodynamic Therapy-Mediated Immune Responses in Three-Dimensional Tumor Models
Abstract
:1. Introduction
2. Comparison of 2D and 3D Tumor Models
3. Methods for 3D Tumor Generation
3.1. Hanging Drop Method
3.2. Liquid Overlay Method
3.3. Bioreactor-Based 3D Culture Method
3.4. Hydrogels
3.5. Magnetic Levitation Method
4. PDT-Induced Antitumor Immune Responses
4.1. PDT and Innate Immune Response
4.2. PDT and Adaptive Immune Response
5. Experimental Studies on Immune Responses to PDT in Cancer Treatment
6. Clinical Studies on PDT Immune Responses in Cancer Treatment
7. Enhancing PDT-Induced Antitumor Immune Responses
7.1. Intracellular Accumulation of PSs
7.2. ER-Targeted PDT
7.3. Mitochondria Targeted PDT
7.4. Application of Nanotechnology
8. Experimental Models for Evaluation of PDT-Induced Antitumor Immune Responses
8.1. Immunomodulation
8.1.1. Immunostimulants
8.1.2. Blocking Immunocompromising (Cellular) Factors
8.1.3. Recognition of Tumor-Associated Antigens (TAA)
9. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
2D | Two-dimensional |
3D | Three-dimensional |
APCs | Antigen-presenting cells |
BCC | Basal cell carcinoma |
BCG | Bacillus Calmette–Geurin |
CLIPT | Continuous low irradiance PDT (CLIPT) |
CRT | Calreticulin |
CTL | Cytotoxic tumor-specific T lymphocytes |
DAMPs | Damage-associated molecular patterns |
DCs | Dendritic cells |
ECM | Extracellular matrix |
EPR | Enhanced permeability and retention |
ER | Endoplasmic reticulum |
ESCC | Esophageal squamous cell carcinoma |
HMGB1 | High-mobility group |
Hsp60 | Heat shock-related proteins |
ICD | Immunogenic cell death |
IL | Interleukins |
IFNγ | Interferon-gamma |
LLC | Lewis lung carcinoma |
MCTS | Multicellular tumor spheroids |
MCWE | Mycobacterium cell wall extract |
MDSCs | Myeloid-derived suppressive cells |
MHC | Major histocompatibility complex |
NK | Natural killer cells |
NP | Nanoparticles |
PBMCs | Peripheral blood mononuclear |
PDT | Photodynamic therapy |
PGE2 | Prostaglandin E2 |
PRRs | Pattern recognition receptors |
PS | Photosensitizer |
ROS | Reactive oxygen species |
TAA | Tumor-associated antigens |
TGF-β | Transforming growth factor beta |
TME | Tumor microenvironment |
TNF-α | Tumor necrosis factor alpha |
TPP | Triphenylphosphonium |
Tregs | Regulatory T cells |
TRL | Toll-like receptor |
VIN | Vulval intraepithelial neoplasia |
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Characteristic | 2D | 3D | Refs. |
---|---|---|---|
In vivo-like | Poor resemblance of the 3D architecture of tumor tissue | Mimic the 3D structure of in vivo tumor tissues | [21] |
Proliferation | Cells grown in monolayers proliferate faster than in 3D tumor models | A relatively slow proliferation rate is similar to that of human tumor cells | [22] |
Polarity | Partial polarization | A precise portrayal of cell polarization | [23] |
Morphology | Flat and sheet-like cells with a stretched appearance | Form aggregated cells. | [24] |
Rigidity | Strong rigid (about 3 × 109 Pascals) | Less rigid (>4000 Pascals) | [25] |
Cellular interactions | Limited cellular interactions and cellular extracellular matrix | Exhibit cellular interactions and cell-extracellular matrix-like solid tumors | [16] |
Gene/protein expression | Alterations in gene expression, mRNA splicing, topology, and biochemistry of cells, often show discrepancies in gene/protein levels when compared to in vivo models | Genes and protein expressions in solid tumors pertinently resemble 3D tumor models | [26,27] |
Response to therapeutics | Monolayer cell cultures are more susceptible to drugs than human tumors | Tumor cells in 3D cultures exhibit drug resistance characteristics similar to those observed in vivo human tumors | [16,26] |
Culture formation | Takes minutes–hours | Take hours–days | [28] |
Culture quality | Good performance, reproducible, long-term culture, ease of interpretation, and culture simplicity | Poor performance and reproducibility, difficult interpretation, and cultures | |
Access to growth factors | Constant exposure of cells to oxygen, nutrients, metabolites, and signaling molecules (as opposed to in vivo) | Limited distribution of oxygen, nutrients, metabolites, and signaling molecules (similar to in vivo) | [16,29] |
Cost of maintenance | Cost-effective, abundant commercially available tests and media | Costly, laborious, and lack of commercially available tests | [30] |
Generation | PS | Localization | Cell Line | Tumor Model | Animal Species | Hallmarks of Immunogenic Cell Death (ICD) In Vitro | Hallmarks of ICD In Vivo | Refs. |
---|---|---|---|---|---|---|---|---|
1st | Photofrin | Mitochondria, cellular membrane | Lewis lung carcinoma (LLC) cells | 2D monolayer cell culture and in vivo | C57BL/6 mice | PDT-treated LLC increased the expression of high-mobility group box-1 (HMGB1) protein in macrophages | PDT accelerated the expression of calreticulin (CRT) and (HMGB1) protein in LLC tumors in vivo. | [48] |
AB12 Mesothelioma | in vivo | Balb/c mice | Localized neutrophil function at 1 h and then drops at 4 h. Increased infiltration of neutrophils at the treated at 24 h | N/A | [49] | |||
2nd | OR141 | Endoplasmic reticulum (ER) | AB12 Mesothelioma | 2D monolayer cell culture, in vivo | Balb/c mice | Maturation of DCs (increased levels of CD80, CD86, CD40 and MHC) | PDT-OR141 showed robust CD8+ and CD4+T responses with increased proliferation, cytotoxic reactions and increased production of interferon-gamma (IFNγ). | [50] |
Mouse SCC7, Human A431 squamous cell carcinoma cells and mouse B16 melanoma cells | 2D monolayer cell culture | N/A | Maturation of DCs (increased expression of MHC-ll+, CD80+ and CD86+) | N/A | [51] | |||
Hypericin | ER | T25 human bladder carcinoma cells | 2D monolayer cell culture | N/A | Maturation of DCs (increased CD80, CD83, CD86, and MCH ll) and functional stimulation (increased NO and L-1β, absent IL-10) | N/A | [52] | |
GL261 glioma cells | 2D monolayer cell culture and in vivo | C57BL/6 mice | Maturation of DCs (elevated levels of CD80, CD86, CD40 and MHC I) | PDT stimulated the accumulation of T-lymphocytes (CD3+, CD4+ and CD8+), TH1 cells, CTLs and TH17 cells at the treated sites | [53] | |||
Rose bengal (RB) | N/A | CT26 colorectal carcinoma cell line | 2D monolayer cell culture and in vivo | Balb/c mice | Upregulation of CRT expression A dose-dependent decrease in ATP Increased extracellular content of HMGB1 Increased expression of HSP90 | PDT-RB stimulated the expression of CRT and HSP90 on tumor cells and the release of HMGB1. | [54] | |
5-Aminolevulinic acid (5-ALA) | ER | PECA squamous cell carcinoma cell line | 2D monolayer cell culture and in vivo | SKH-1 mice | Maturation of DCs (upregulation of MHC-II, DC80, and CD86) and increased production of IFN-γ and IL-12 | PDT upregulated expression of CD80, CD86, and MHC-II and induced T cell proliferation | [55] | |
PECA squamous cell carcinoma cell line | 2D monolayer cell culture and in vivo | SKH-1 mice | PDT improved the expression of CRT, HSP70, and HMGB1 | Simulated phenotypic maturation (increased MHCII, CD80, and CD86) | [56] | |||
Glioblastoma (GB) cell lines U87 and U251 | 3D tumor spheroids | N/A | Maturation of DCs (increased levels of CD40, CD80, CD83, and CD86) | N/A | [57] | |||
PECA squamous cell carcinoma | in vivo | SKH-1 mice | N/A | Infiltration of T-lymphocytes (CD4+/CD8+) at 7 days | [58] | |||
Redaporfin | ER and Golgi apparatus GA | CT26 colorectal carcinoma cell line | in vivo | Balb/c mice | N/A | PDT resulted in a strong neutrophilia (2–24 h), the systemic elevation of IL-6 (24 h), increased number of CD4+ and CD8+ T cells, as well as increased production of IFN-γ or CD69+. | [59] | |
Photodithazine | ER and Golgi apparatus | GL261 murine glioma, MCA205 murine sarcoma | 2D monolayer cell culture and in vivo | C57BL/6J | Maturation of DCs (increased CD40, CD86, and MHC II) and increase in IL-6 | PDT stimulated the release of calreticulin, HMGB1 and ATP, which activated the production of IL-6. | [60] | |
3rd | Core–shell gold nanocage coated with manganese dioxide and hyaluronic acid (AMH) | Hyaluronic acid targets CD44-overexpressed on the plasma membrane of CT26 cancer cells | CT26 colorectal carcinoma cell line | 2D monolayer cell culture | N/A | Maturation of DCs (upregulation of CD83, CD86, MHC II) | N/A | [61] |
Cetuximab-IR700 | Cetuximab binds to HER1-overexpressed on the plasma membrane of cancer cells | A431 human epidermoid carcinoma | 2D monolayer cell culture and in vivo | Athymic nude mice | Maturation of DCs (increased expression of CD80, CD86, MHC II) and increased production of IL-12 | Increased population of CD86+ DCs, CD11c, CD205, and MHC II positive cells. | [62] | |
Core–shell gold nanocage@manganese dioxide (AuNC@MnO2, AM) | N/A | 4T1 murine mammary carcinoma | 2D monolayer cell culture and in vivo | Balb/c mice | Maturation of DCs (overexpression of CD83, and CD86) and increased production of IL-12 | PDT resulted in intratumoral increase in CD11c+CD86+ and CD11c+CD83+ DCs, as well as increased NK cells and CD8+ and CD4+ | [63] | |
Hybrid protein oxygen nanocarrier with chlorin e6 encapsulated (C@HPOC) | N/A | 4T1 murine mammary carcinoma | 2D monolayer cell culture and in vivo | Balb/c mice | Maturation of DCs (increased CD86 and MHC II) | An influx of NK cells, T cells (CD8+ CD4+) at the tumor site, and maturation of DCs. | [64] | |
Benzoporphyrin Derivative nanoconjugates modified with cetuximab, transferrin and trastuzumab | Cetuximab binds with anti-EGFR mAb, transferrin with glycoprotein and trastuzumab binds with anti-HER-2 mAb | PDAC Pancreatic cancer cells | 3D tumor spheroids | N/A | PDT triggered the expression of heat shock-related proteins (Hsp60, Hsp70), caltreticulin and high-mobility group box 1 in light intensity and time-dependent manner. A similar trend was observed in CD4+ and CD8+ T cells antitumor reactivity by upregulating CD107a and IFN-γ | N/A | [65] | |
5-ALAdoamine) dendrimers generation two (PAMAM-G2) | Endo-lysosomes and mitochondria | B16 and A375 metastatic melanoma cells | in vivo | C57BL6J mice | N/A | Prevented tumor metastases. Inhibited tumor-recurrence. Infiltration of CD4+ CD8+ T cells at the tumor region, predominately central memory T cells (CD44high CD62Lhigh). Insignificant change of CD3+ T cells in the spleen. Increased levels of TNF-α and IFN-γ in serum. Maintained immune balance and prolonged recurrence-free survival | [66] | |
Aluminum-phthalocyanine nanoemulsion (AlPcNE) | N/A | B16F10 cells | in vivo | C57BL/6 mice | N/A | PDT-AlPcNE induced a significant release of HMGB1 and ATP as well as the expression of CRT on the plasma membrane | [67] |
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Nkune, N.W.; Simelane, N.W.N.; Montaseri, H.; Abrahamse, H. Photodynamic Therapy-Mediated Immune Responses in Three-Dimensional Tumor Models. Int. J. Mol. Sci. 2021, 22, 12618. https://doi.org/10.3390/ijms222312618
Nkune NW, Simelane NWN, Montaseri H, Abrahamse H. Photodynamic Therapy-Mediated Immune Responses in Three-Dimensional Tumor Models. International Journal of Molecular Sciences. 2021; 22(23):12618. https://doi.org/10.3390/ijms222312618
Chicago/Turabian StyleNkune, Nkune Williams, Nokuphila Winifred Nompumelelo Simelane, Hanieh Montaseri, and Heidi Abrahamse. 2021. "Photodynamic Therapy-Mediated Immune Responses in Three-Dimensional Tumor Models" International Journal of Molecular Sciences 22, no. 23: 12618. https://doi.org/10.3390/ijms222312618