Table 1.
The evidence of immunogenic cell death induction by Type I and Type II in cancer
| ICD inducer | Cellular target for cell death induction | Evidence of antitumor immunity in patients connected to ICD determinants |
|---|---|---|
| Type I | ||
| Anthracyclines, Mitoxantrone | DNA or proteins of DNA replication machinery | Breast cancer patients bearing a wt P2RX7 allele25 or a wt TLR4 allele7 benefited more from anthracycline therapy in comparison to those bearing mutated allele. |
| 7A7 (EGFR-specific antibody) | EGFR | ND |
| Bortezomib | ERAD, 26S proteasome, CIP2A | Bortezomib improves progression-free survival in multiple myeloma patients overexpressing PRAME antigen124 |
| Cardiac glycosides (CGs)* | Na+, K+-ATPase in plasma membrane | Retrospectively, a positive impact of administration of the cardiac glycosides digoxin during chemotherapy on overall survival in cohorts of breast, colorectal, head and neck, and hepatocellular carcinoma patients has been shown44 |
| Cyclophosphamide † | DNA | CTX induced a slight decrease of Tregs in the blood of patients with metastatic carcinoma treated with CTX (in combinantion with BCG injected in metastasis)125 |
| CTX induced drop in B-cell counts, without affecting the number of T cells in cancer patients126 | ||
| Oxaliplatin | DNA synthesis | Patients bearing loss-of-function allele of TLR4 showed shorter progression-free survival and overall survival in comparison with patients bearing WT allele of the TLR440 |
| Shikonin | Tumor-specific pyruvate kinase-M2 protein, 20S subunit of proteasome | Initiation of clinical study (breast cancer NCT01287468) |
| UVC irradiation | DNA | ND |
| γ-irradiation | DNA | Better survival of patients with esophageal squamous cell carcinoma (ESCC) after radiotherapy and chemotherapy treatment (increased HMBG1 in serum)57 |
| Septacidin | Cellular Proteins possibly Nrf2 and Tyrosyl-DNA phosphodiesterase | ND |
| Bleomycin‡ | DNA | ND |
| High hydrostatic pressure | Cellular proteins | ND |
| Wogonin | Mitochondria | ND |
| Vorinostat (histone deacetylase inhibitor) | Histones (Nucleus) | ND |
| Type II | ||
| Hypericin-based Photodynamic therapy | Endoplasmic reticulum | ND |
| Various Oncolytic Viruses | Endoplasmic reticulum | ND |
*It is important to note that CGs alone are unable to induce ICD in vivo; for that to happen they need to be combined with other chemotherapeutics although those can be non-ICD inducers whose immunogenicity can be reinstated by CGs.
† Immunopotentiating effects of cyclophosphamide are highly dose dependent in both humans as well as preclinical animal models. Metronomic doses of cyclophoshamide have been found to be “ICD-supportive” however high doses can be strongly immunosuppressive.
‡ Bleomycin has been shown to exert ambivalent immune effects since along with ICD induction it paradoxically also induces proliferation of immunosuppressive Treg cells.
Abbreviations: CG, cardiac glycosides; CIP2A, cancerous inhibitor of PP2A; CTX, cyclophosphamide; EGFR, epidermal growth factor receptor; ESCC, esophageal squamous cell carcinoma; ERAD, endoplasmic-reticulum-associated protein degradation; HMGB1, high mobility group box 1; ICD, immunogenic cell death; ND, not defined; NDV, Newcastle disease virus; Nrf2, nuclear factor erythroid 2-related factor; PRAME, preferentially expressed antigen of melanoma; P2RX7, P2X purinoceptor 7; TLR4, toll like receptor 4; Treg, regulatory T cell; UVC, UV light C.