Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer
Abstract
Simple Summary
Abstract
1. Introduction
2. Cell Death Modalities and Immunogenicity
3. Immunomodulation by Conventional Anticancer Agents
3.1. Anthracyclines
3.2. Taxanes
3.3. Cyclophosphamide
3.4. Methotrexate
3.5. 5-Fluorouracil
3.6. Capecitabine
3.7. Trastuzumab
3.8. Pertuzumab
3.9. Trastuzumab Emtansine
4. Molecular Characteristics of Anticancer Agent-Induced ICD
5. Immunogenic Modulation by Anticancer Agents as Non-Classical ICD
6. Roles of DAMPs and ICD in the Clinical Significance of Breast Cancer
7. Exploiting the Double-Edged Sword of DAMPs for Antitumor Immunity
8. Immunomodulatory Effects of Anticancer Agents and the Enhancement of Antitumor Immunity in Combination with Immune Checkpoint Inhibitors
9. ICD and Long-Term Antitumor Immune Memory
10. Future Therapies
11. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Anticancer Agents | Mechanism of Action | Immunomodulatory Effect |
---|---|---|
Anthracyclines | ||
Doxorubicin | Interferes with the correct unwinding of DNA during replication and transcription | Production of IFN-γ by CTLs, production of IL-17 by γδ T cells and promotion of CTL accumulation by γδ T cells, and IL-1β induction [20,21]. Reduction of MDSCs [22]. Increase in CD4, CD8, and NK cells and expression of IFN-γ, perforin, and granzyme B [22]. |
Epirubicin | Inhibits the synthesis of nucleic acids and proteins, and forms complexes with DNA by base pair intercalation, thereby inhibiting topoisomerase II activity Promotes ICD | |
Alkylating agent | ||
Cyclophosphamide | Suppresses protein synthesis by inhibiting the transcription of DNA to RNA Promotes ICD | Suppression of Tregs at low dose and Increase in tumor-specific T cells [23]. Increase in MDSCs due to AC as a paradoxical effect [24,25]. |
Antimetabolites | ||
Methotrexate | Inhibits dihydrofolate reductase | Maintenance of the ability of DCs to produce pro-inflammatory cytokines and activate NK and T cells [26]. Combination with methotrexate and Tc1 cell transfer increases TILs and decreases Tregs [27]. |
5-Fluorouracil | Inhibits DNA and RNA synthesis | Promotion of antigen uptake by DCs and enhanced cytotoxicity of NK and CD8+ T cells [28]. Elimination of MDSCs [29]. |
Capecitabine | Prodrug that converts 5′-deoxy-5-fluorouridine to 5-fluorouracil Inhibits DNA and RNA synthesis | Release of antigens by tumor cell death, activation of DCs, presentation of tumor antigens to T cells [30]. Depletion of MDSCs, alleviation of NK and T cell suppression [31] |
Taxanes | ||
Paclitaxel | Changes tubulin polymerization or depolymerization | Increased levels of IFN-γ, IL-2, IL-6, GM-CSF, and pNK cell activity [32]. Decreased Tregs, independently of TLR4 [33]. Increased permeability of granzyme B by perforin independent CTLs [34]. |
Nab-paclitaxel | Paclitaxel bound to albumin nanoparticles. Transport of albumin by transcytosis increases its delivery to tumors | |
Docetaxel | Promotes immunogenic modulation | Leads MDSCs to transform from the M2 to the M1 phenotype via STAT3 [35]. |
Targeting agents | ||
Trastuzumab | Inhibits signals transmitted by HER-2 and degrades HER-2 | Enhanced cytotoxicity of HER-2-specific CD8+CTLs [36]. Increase in tumor-associated NK cells and lymphocytes expressing granzyme B and TiA1 [37]. ADCC mediated by FcγRIII receptor [38]. |
Pertuzumab | Inhibits dimerization between HER-2 and HER family receptors | Activation of ADCC [39]. Mobilization of NK cells by ADCC [40]. Complement- and macrophage-mediated cytotoxicity [41]. |
Trastuzumab-emtansine | Taken up by endosomes and degraded, releasing T-DM1 Blocks the HER-2 signaling pathway and mediates ADCC | DC maturation and production of proinflammatory cytokines by ansamitocin P3. Enhanced antigen uptake and activation of tumor-specific T cells in tumor-draining lymph nodes [42,43]. Massive infiltration of T cells, polarization of Th1 cells, and increases in Tregs in combination with anti-CTLA-4/PD-1 agents [43]. |
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Kim, R.; Kin, T. Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer. Cancers 2021, 13, 4756. https://doi.org/10.3390/cancers13194756
Kim R, Kin T. Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer. Cancers. 2021; 13(19):4756. https://doi.org/10.3390/cancers13194756
Chicago/Turabian StyleKim, Ryungsa, and Takanori Kin. 2021. "Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer" Cancers 13, no. 19: 4756. https://doi.org/10.3390/cancers13194756
APA StyleKim, R., & Kin, T. (2021). Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer. Cancers, 13(19), 4756. https://doi.org/10.3390/cancers13194756