Skip to main content
Top
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Cytokines | Research article

Hormetic and synergistic effects of cancer treatments revealed by modelling combinations of radio - or chemotherapy with immunotherapy

Authors: Sanyi Tang, Shuo Li, Biao Tang, Xia Wang, Yanni Xiao, Robert A. Cheke

Published in: BMC Cancer | Issue 1/2023

Login to get access

Abstract

Background

Radio/chemotherapy and immune systems provide examples of hormesis, as tumours can be stimulated (or reduced) at low radio/chemical or antibody doses but inhibited (or stimulated) by high doses.

Methods

Interactions between effector cells, tumour cells and cytokines with pulsed radio/chemo-immunotherapy were modelled using a pulse differential system.

Results

Our results show that radio/chemotherapy (dose) response curves (RCRC) and/or immune response curves (IRC) or a combination of both, undergo homeostatic changes or catastrophic shifts revealing hormesis in many parameter regions. Some mixed response curves had multiple humps, posing challenges for interpretation of clinical trials and experimental design, due to a fuzzy region between an hormetic zone and the toxic threshold. Mixed response curves from two parameter bifurcation analyses demonstrated that low-dose radio/chemotherapy and strong immunotherapy counteract side-effects of radio/chemotherapy on effector cells and cytokines and stimulate effects of immunotherapy on tumour growth. The implications for clinical applications were confirmed by good fits to our model of RCRC and IRC data.

Conclusions

The combination of low-dose radio/chemotherapy and high-dose immunotherapy is very effective for many solid tumours. The net benefit and synergistic effect of combined therapy is conducive to the treatment and inhibition of tumour cells.
Appendix
Available only for authorised users
Literature
1.
go back to reference Gabrilovich DI. Combination of chemotherapy and immunotherapy for cancer: a paradigm revisited. Lancet Oncol. 2007;8:1–3.CrossRef Gabrilovich DI. Combination of chemotherapy and immunotherapy for cancer: a paradigm revisited. Lancet Oncol. 2007;8:1–3.CrossRef
2.
go back to reference Genar G, Lucas S, Michiels C. Reprogramming of tumor-associated macrophages with anticancer therapies: radiotherapy versus chemo- and immunotherapies. Front Immun. 2017;8:828.CrossRef Genar G, Lucas S, Michiels C. Reprogramming of tumor-associated macrophages with anticancer therapies: radiotherapy versus chemo- and immunotherapies. Front Immun. 2017;8:828.CrossRef
3.
4.
go back to reference Slovin S. Chemotherapy and immunotherapy combination in advanced prostate cancer. Clin Adv Hematol Oncol. 2012;10:90–100.PubMed Slovin S. Chemotherapy and immunotherapy combination in advanced prostate cancer. Clin Adv Hematol Oncol. 2012;10:90–100.PubMed
5.
6.
go back to reference Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest. 2000;105:1045–7.CrossRefPubMedPubMedCentral Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest. 2000;105:1045–7.CrossRefPubMedPubMedCentral
7.
go back to reference Kirschner D, Panetta JC. Modeling immunotherapy of the tumor-immune interaction. J Math Biol. 1998;37:235–52.CrossRefPubMed Kirschner D, Panetta JC. Modeling immunotherapy of the tumor-immune interaction. J Math Biol. 1998;37:235–52.CrossRefPubMed
8.
go back to reference Lakmechea A, Arino O. Nonlinear mathematical model of pulsed-therapy of heterogeneous tumors. Nonlinear Analysis: RWA. 2001;2:455–65. Lakmechea A, Arino O. Nonlinear mathematical model of pulsed-therapy of heterogeneous tumors. Nonlinear Analysis: RWA. 2001;2:455–65.
9.
go back to reference Bunimovich-Mendrazitsky S, Byrne H, Stone L. Mathematical model of pulsed immunotherapy for superficial bladder cancer. Bull Math Biol. 2008;70:2055–76.CrossRefPubMed Bunimovich-Mendrazitsky S, Byrne H, Stone L. Mathematical model of pulsed immunotherapy for superficial bladder cancer. Bull Math Biol. 2008;70:2055–76.CrossRefPubMed
10.
go back to reference Scott BR. Low-dose radiation-induced protective process and implications for risk assessment, cancer prevention, and cancer therapy. Dose-Response. 2007;5:131–49.CrossRefPubMedPubMedCentral Scott BR. Low-dose radiation-induced protective process and implications for risk assessment, cancer prevention, and cancer therapy. Dose-Response. 2007;5:131–49.CrossRefPubMedPubMedCentral
11.
go back to reference Scott BR. Radiation-hormesis phenotypes, the related mechanisms and implications for disease prevention and therapy. J Cell Commun Signal. 2014;8:341–52.CrossRefPubMedPubMedCentral Scott BR. Radiation-hormesis phenotypes, the related mechanisms and implications for disease prevention and therapy. J Cell Commun Signal. 2014;8:341–52.CrossRefPubMedPubMedCentral
12.
go back to reference Yang LW, Jiang H, Liang X, et al. Low-dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics. Int J Cancer. 2016;139:2157–68.CrossRefPubMed Yang LW, Jiang H, Liang X, et al. Low-dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics. Int J Cancer. 2016;139:2157–68.CrossRefPubMed
13.
go back to reference de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nature Rev Cancer. 2006;6:24–37.CrossRef de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nature Rev Cancer. 2006;6:24–37.CrossRef
14.
go back to reference Edward J, et al. Hormesis outperforms threshold model in national cancer institute antitumor drug screening database. Toxicol Sci. 2006;94:368–78.CrossRef Edward J, et al. Hormesis outperforms threshold model in national cancer institute antitumor drug screening database. Toxicol Sci. 2006;94:368–78.CrossRef
15.
go back to reference Salazar-Onfray F, Lòpez MN, Mendoza-Naranjo A. Paradoxical effects of cytokines in tumor immune surveillance and tumor immune escape. Cytokine Growth F R. 2007;18:171–82.CrossRef Salazar-Onfray F, Lòpez MN, Mendoza-Naranjo A. Paradoxical effects of cytokines in tumor immune surveillance and tumor immune escape. Cytokine Growth F R. 2007;18:171–82.CrossRef
17.
go back to reference Pearce OMT, Lfubli H, Verhagen A, et al. Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies. Proc Natl Acad Sci USA. 2014;111:5998–6003.CrossRefPubMedPubMedCentral Pearce OMT, Lfubli H, Verhagen A, et al. Inverse hormesis of cancer growth mediated by narrow ranges of tumor-directed antibodies. Proc Natl Acad Sci USA. 2014;111:5998–6003.CrossRefPubMedPubMedCentral
20.
go back to reference Cui JW, Yang GZ, Pan ZY, et al. Hormetic response to low-dose radiation: focus on the immune system and its clinical implications. Int J Mol Sci. 2017;18:280.CrossRefPubMedPubMedCentral Cui JW, Yang GZ, Pan ZY, et al. Hormetic response to low-dose radiation: focus on the immune system and its clinical implications. Int J Mol Sci. 2017;18:280.CrossRefPubMedPubMedCentral
21.
23.
go back to reference Calabrese EJ, Giordano JJ, Kozumbo WJ, et al. Hormesis mediates dose-sensitive shifts in macrophage activation patterns. Pharmacol Res. 2018;137:236–49.CrossRefPubMed Calabrese EJ, Giordano JJ, Kozumbo WJ, et al. Hormesis mediates dose-sensitive shifts in macrophage activation patterns. Pharmacol Res. 2018;137:236–49.CrossRefPubMed
24.
go back to reference Calabrese EJ, Blain R. The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview. Toxicol Appl Pharm. 2005;202:289–301.CrossRef Calabrese EJ, Blain R. The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview. Toxicol Appl Pharm. 2005;202:289–301.CrossRef
25.
go back to reference Tang S, Liang J, Xiang C, Xiao Y, Wang X, Wu J, Li G, Cheke RA. A general model of hormesis in biological systems and its application to pest management. J Roy Soc Interface. 2019;16:20190468.CrossRef Tang S, Liang J, Xiang C, Xiao Y, Wang X, Wu J, Li G, Cheke RA. A general model of hormesis in biological systems and its application to pest management. J Roy Soc Interface. 2019;16:20190468.CrossRef
26.
go back to reference Zhang J, Liu SS, Zhu XW. Benefits from hazards: mixture hormesis induced by emim Cl despite its individual inhibitions. Chemosphere. 2014;112:420–6.CrossRefPubMed Zhang J, Liu SS, Zhu XW. Benefits from hazards: mixture hormesis induced by emim Cl despite its individual inhibitions. Chemosphere. 2014;112:420–6.CrossRefPubMed
27.
go back to reference Wei H, Lin J. Periodically pulsed immunotherapy in a mathematical model of tumor-immune interaction. Int J Bifurcat Chaos. 2013;23:1350068.CrossRef Wei H, Lin J. Periodically pulsed immunotherapy in a mathematical model of tumor-immune interaction. Int J Bifurcat Chaos. 2013;23:1350068.CrossRef
28.
go back to reference Yang J, Tang S, Cheke RA. Modelling pulsed immunotherapy of tumour-immune interaction. Math Comput Simulat. 2015;109:92–112.CrossRef Yang J, Tang S, Cheke RA. Modelling pulsed immunotherapy of tumour-immune interaction. Math Comput Simulat. 2015;109:92–112.CrossRef
29.
30.
go back to reference Kovacs E. The serum levels of IL-12 and IL-16 in cancer patients. Relation to the tumour stage and previous therapy. Biomed Pharmacother. 2001;55:111–6.CrossRefPubMed Kovacs E. The serum levels of IL-12 and IL-16 in cancer patients. Relation to the tumour stage and previous therapy. Biomed Pharmacother. 2001;55:111–6.CrossRefPubMed
31.
go back to reference Xian JM, Yang H, Lin YH, Liu SX. Combination nonviral murine interleukin 2 and interleukin 12 gene therapy and radiotherapy for head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2005;131:1079–85.CrossRefPubMed Xian JM, Yang H, Lin YH, Liu SX. Combination nonviral murine interleukin 2 and interleukin 12 gene therapy and radiotherapy for head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2005;131:1079–85.CrossRefPubMed
32.
go back to reference Girel S, Crauste F. Existence and stability of periodic solutions of an impulsive differential equation and application to CD8 T-cell differentiation. J Math Biol. 2018;76:1765–95.CrossRefPubMed Girel S, Crauste F. Existence and stability of periodic solutions of an impulsive differential equation and application to CD8 T-cell differentiation. J Math Biol. 2018;76:1765–95.CrossRefPubMed
33.
go back to reference Yoshimasu T, Ohashi T, Oura S, et al. A theoretical model for the hormetic dose-response curve for anticancer agents. Anticancer Res. 2015;35:5851–6.PubMed Yoshimasu T, Ohashi T, Oura S, et al. A theoretical model for the hormetic dose-response curve for anticancer agents. Anticancer Res. 2015;35:5851–6.PubMed
34.
go back to reference Lee DW, et al. ASTCT Consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Tr. 2019;25:625–38.CrossRef Lee DW, et al. ASTCT Consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Tr. 2019;25:625–38.CrossRef
35.
go back to reference Antonia SJ, Mirza N, Fricke I, et al. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin Cancer Res. 2006;12:878–87.CrossRefPubMed Antonia SJ, Mirza N, Fricke I, et al. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin Cancer Res. 2006;12:878–87.CrossRefPubMed
36.
go back to reference Reck M, Ciuleanu T-E, Cobo M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC):CheckMate 9LA. J Clin Oncol. 2021;39(15):9501–9501. Reck M, Ciuleanu T-E, Cobo M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC):CheckMate 9LA. J Clin Oncol. 2021;39(15):9501–9501.
37.
go back to reference Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. New England J Med. 2017;377(20):1919–29.CrossRef Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. New England J Med. 2017;377(20):1919–29.CrossRef
38.
go back to reference Faivre-Finn C, Vicente D, Kurata T, et al. LBA49 Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial. Ann Oncol. 2020;31:S1178–9.CrossRef Faivre-Finn C, Vicente D, Kurata T, et al. LBA49 Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial. Ann Oncol. 2020;31:S1178–9.CrossRef
39.
go back to reference Novello S, Kowalski DM, Luft A, et al. 974MO 5-year update from KEYNOTE-407: Pembrolizumab plus chemotherapy in squamous non-small cell lung cancer (NSCLC). Ann Oncol. 2022;33:S993–4.CrossRef Novello S, Kowalski DM, Luft A, et al. 974MO 5-year update from KEYNOTE-407: Pembrolizumab plus chemotherapy in squamous non-small cell lung cancer (NSCLC). Ann Oncol. 2022;33:S993–4.CrossRef
Metadata
Title
Hormetic and synergistic effects of cancer treatments revealed by modelling combinations of radio - or chemotherapy with immunotherapy
Authors
Sanyi Tang
Shuo Li
Biao Tang
Xia Wang
Yanni Xiao
Robert A. Cheke
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-11542-6

Other articles of this Issue 1/2023

BMC Cancer 1/2023 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine