Review
. 2018 Dec; 10(12):.
doi: 10.3390/cancers10120515.

Radiotherapy as a New Player in Immuno-Oncology

Shang-Jui Wang 1 Bruce Haffty 2 
Affiliations
  • PMID: 30558196
  •     142 References
  •     6 citations

Abstract

Recent development in radiation biology has revealed potent immunogenic properties of radiotherapy in cancer treatments. However, antitumor immune effects of radiotherapy are limited by the concomitant induction of radiation-dependent immunosuppressive effects. In the growing era of immunotherapy, combining radiotherapy with immunomodulating agents has demonstrated enhancement of radiation-induced antitumor immune activation that correlated with improved treatment outcomes. Yet, how to optimally deliver combination therapy regarding dose-fractionation and timing of radiotherapy is largely unknown. Future prospective testing to fine-tune this promising combination of radiotherapy and immunotherapy is warranted.

Keywords: cancer; combination therapy; dose-fractionation; immunotherapy; radiation; radiotherapy; timing.

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Oncotarget, 2016 Feb 26; 7(14). PMID: 26910282    Free PMC article.
Highly Cited.
Immunocytokines for cancer treatment: past, present and future.
Dario Neri, Paul M Sondel.
Curr Opin Immunol, 2016 Apr 10; 40. PMID: 27060634    Free PMC article.
Review.
Concomitant targeting of programmed death-1 (PD-1) and CD137 improves the efficacy of radiotherapy in a mouse model of human BRAFV600-mutant melanoma.
Paula Kroon, Jules Gadiot, +7 authors, Inge Verbrugge.
Cancer Immunol Immunother, 2016 May 11; 65(6). PMID: 27160390    Free PMC article.
Optimizing Timing of Immunotherapy Improves Control of Tumors by Hypofractionated Radiation Therapy.
Kristina H Young, Jason R Baird, +9 authors, Marka R Crittenden.
PLoS One, 2016 Jun 10; 11(6). PMID: 27281029    Free PMC article.
Highly Cited.
Enhanced binding of necrosis-targeting immunocytokine NHS-IL12 after local tumour irradiation in murine xenograft models.
Franziska Eckert, Julia Schmitt, +6 authors, Karin Schilbach.
Cancer Immunol Immunother, 2016 Jul 05; 65(8). PMID: 27376889
Local Tumor Treatment in Combination with Systemic Ipilimumab Immunotherapy Prolongs Overall Survival in Patients with Advanced Malignant Melanoma.
Sebastian Theurich, Sacha I Rothschild, +16 authors, Max Schlaak.
Cancer Immunol Res, 2016 Jul 29; 4(9). PMID: 27466265
4-1BB Aptamer-Based Immunomodulation Enhances the Therapeutic Index of Radiation Therapy in Murine Tumor Models.
Ana Paula Benaduce, Randall Brenneman, +3 authors, Adrian Ishkanian.
Int J Radiat Oncol Biol Phys, 2016 Sep 07; 96(2). PMID: 27598810
Trial Watch: Immunotherapy plus radiation therapy for oncological indications.
Erika Vacchelli, Norma Bloy, +13 authors, Lorenzo Galluzzi.
Oncoimmunology, 2016 Oct 21; 5(9). PMID: 27757313    Free PMC article.
Review.
Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial.
Antonin Levy, Christophe Massard, Jean-Charles Soria, Eric Deutsch.
Eur J Cancer, 2016 Oct 21; 68. PMID: 27764686
Suppression of Type I IFN Signaling in Tumors Mediates Resistance to Anti-PD-1 Treatment That Can Be Overcome by Radiotherapy.
Xiaohong Wang, Jonathan E Schoenhals, +18 authors, James W Welsh.
Cancer Res, 2016 Nov 09; 77(4). PMID: 27821490    Free PMC article.
Highly Cited.
The TLR7 agonist imiquimod induces anti-cancer effects via autophagic cell death and enhances anti-tumoral and systemic immunity during radiotherapy for melanoma.
Jeong Hyun Cho, Hyo-Ji Lee, +10 authors, Yu-Jin Jung.
Oncotarget, 2017 Feb 18; 8(15). PMID: 28212561    Free PMC article.
PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity.
Sydney R Gordon, Roy L Maute, +10 authors, Irving L Weissman.
Nature, 2017 May 18; 545(7655). PMID: 28514441    Free PMC article.
Highly Cited.
Fractionated Radiation Therapy Stimulates Antitumor Immunity Mediated by Both Resident and Infiltrating Polyclonal T-cell Populations when Combined with PD-1 Blockade.
Simon J Dovedi, Eleanor J Cheadle, +11 authors, Timothy M Illidge.
Clin Cancer Res, 2017 May 24; 23(18). PMID: 28533222
Highly Cited.
Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.
Narek Shaverdian, Aaron E Lisberg, +5 authors, Percy Lee.
Lancet Oncol, 2017 May 30; 18(7). PMID: 28551359    Free PMC article.
Highly Cited.
DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity.
Claire Vanpouille-Box, Amandine Alard, +7 authors, Sandra Demaria.
Nat Commun, 2017 Jun 10; 8. PMID: 28598415    Free PMC article.
Highly Cited.
Tumor-targeted IL-12 combined with local irradiation leads to systemic tumor control via abscopal effects in vivo.
Franziska Eckert, Ivan Jelas, +8 authors, Karin Schilbach.
Oncoimmunology, 2017 Jul 07; 6(6). PMID: 28680762    Free PMC article.
Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy.
Michael A Cannarile, Martin Weisser, +3 authors, Dominik Rüttinger.
J Immunother Cancer, 2017 Jul 19; 5(1). PMID: 28716061    Free PMC article.
Highly Cited. Review.
Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.
Scott J Antonia, Augusto Villegas, +28 authors, PACIFIC Investigators.
N Engl J Med, 2017 Sep 09; 377(20). PMID: 28885881
Highly Cited.
Abscopal, immunological effects of radiotherapy: Narrowing the gap between clinical and preclinical experiences.
Nikko Brix, Anna Tiefenthaller, +2 authors, Kirsten Lauber.
Immunol Rev, 2017 Oct 14; 280(1). PMID: 29027221
Highly Cited. Review.
TAMeless traitors: macrophages in cancer progression and metastasis.
Shweta Aras, M Raza Zaidi.
Br J Cancer, 2017 Oct 25; 117(11). PMID: 29065107    Free PMC article.
Highly Cited. Review.
Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma.
H B Stone, L J Peters, L Milas.
J Natl Cancer Inst, 1979 Nov 01; 63(5). PMID: 291749
Highly Cited.
Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics.
Abhishek D Garg, Sanket More, +6 authors, Lorenzo Galluzzi.
Oncoimmunology, 2017 Dec 07; 6(12). PMID: 29209573    Free PMC article.
Highly Cited. Review.
Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors.
Jason J Luke, Jeffrey M Lemons, +17 authors, Steven J Chmura.
J Clin Oncol, 2018 Feb 14; 36(16). PMID: 29437535    Free PMC article.
Highly Cited.
A systematic review of the influence of radiation-induced lymphopenia on survival outcomes in solid tumors.
Bhanu Prasad Venkatesulu, Supriya Mallick, Steven H Lin, Sunil Krishnan.
Crit Rev Oncol Hematol, 2018 Feb 28; 123. PMID: 29482778
Highly Cited. Systematic Review.
Transplantable Melanomas in Hamsters and Gerbils as Models for Human Melanoma. Sensitization in Melanoma Radiotherapy-From Animal Models to Clinical Trials.
Martyna Śniegocka, Ewa Podgórska, +9 authors, Krystyna Urbańska.
Int J Mol Sci, 2018 Apr 05; 19(4). PMID: 29614755    Free PMC article.
Review.
The immunocytokine L19-IL2: An interplay between radiotherapy and long-lasting systemic anti-tumour immune responses.
Nicolle H Rekers, Veronica Olivo Pimentel, +8 authors, Philippe Lambin.
Oncoimmunology, 2018 Apr 11; 7(4). PMID: 29632732    Free PMC article.
Radiation Followed by OX40 Stimulation Drives Local and Abscopal Antitumor Effects in an Anti-PD1-Resistant Lung Tumor Model.
Sharareh Niknam, Hampartsoum B Barsoumian, +15 authors, James W Welsh.
Clin Cancer Res, 2018 May 23; 24(22). PMID: 29784675    Free PMC article.
Radiotherapy and CD40 Activation Separately Augment Immunity to Checkpoint Blockade in Cancer.
Andrew J Rech, Hannah Dada, +4 authors, Robert H Vonderheide.
Cancer Res, 2018 May 31; 78(15). PMID: 29844122    Free PMC article.
Radiation and Local Anti-CD40 Generate an Effective in situ Vaccine in Preclinical Models of Pancreatic Cancer.
Sayeda Yasmin-Karim, Patrick T Bruck, +6 authors, Wilfred Ngwa.
Front Immunol, 2018 Sep 25; 9. PMID: 30245691    Free PMC article.
Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC.
Scott J Antonia, Augusto Villegas, +31 authors, PACIFIC Investigators.
N Engl J Med, 2018 Oct 04; 379(24). PMID: 30280658
Highly Cited.
Radiotherapy induces responses of lung cancer to CTLA-4 blockade.
Silvia C Formenti, Nils-Petter Rudqvist, +15 authors, Sandra Demaria.
Nat Med, 2018 Nov 07; 24(12). PMID: 30397353    Free PMC article.
Highly Cited.
Inhibition of cell growth in synchronous human hypernephroma cells by recombinant interferon alpha-D and irradiation.
A Y Chang, P C Keng.
J Interferon Res, 1983 Jan 01; 3(4). PMID: 6672111
Transforming growth factor-beta activation in irradiated murine mammary gland.
M H Barcellos-Hoff, R Derynck, M L Tsang, J A Weatherbee.
J Clin Invest, 1994 Feb 01; 93(2). PMID: 8113421    Free PMC article.
Highly Cited.
Induction of the expression of the interleukin-1 beta gene in mouse spleen by ionizing radiation.
H Ishihara, K Tsuneoka, A B Dimchev, M Shikita.
Radiat Res, 1993 Mar 01; 133(3). PMID: 8383862
Radiation-enhanced expression of major histocompatibility complex class I antigen H-2Db in B16 melanoma cells.
S H Hauser, L Calorini, D E Wazer, S Gattoni-Celli.
Cancer Res, 1993 Apr 15; 53(8). PMID: 8467514
Cell adhesion molecules mediate radiation-induced leukocyte adhesion to the vascular endothelium.
D Hallahan, J Kuchibhotla, C Wyble.
Cancer Res, 1996 Nov 15; 56(22). PMID: 8912850
Phase I dose-escalation study of tumor necrosis factor-alpha and concomitant radiation therapy.
D E Hallahan, E E Vokes, +6 authors, R R Weichselbaum.
Cancer J Sci Am, 1995 Oct 01; 1(3). PMID: 9166477
Dendritic cells as adjuvants for immune-mediated resistance to tumors.
G Schuler, R M Steinman.
J Exp Med, 1998 Feb 12; 186(8). PMID: 9379142    Free PMC article.
Review.
Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs.
M L Albert, B Sauter, N Bhardwaj.
Nature, 1998 Mar 24; 392(6671). PMID: 9510252
Highly Cited.
The Association of Radiation Dose-Fractionation and Immunotherapy Use With Overall Survival in Metastatic Melanoma Patients.
Shang-Jui Wang, Sachin R Jhawar, +7 authors, Sharad Goyal.
Cureus, 2020 Jul 28; 12(6). PMID: 32714704    Free PMC article.
Optimizing radiotherapy with immune checkpoint blockade in hepatocellular carcinoma.
Changhoon Choi, Gyu Sang Yoo, Won Kyung Cho, Hee Chul Park.
World J Gastroenterol, 2019 Jun 07; 25(20). PMID: 31171886    Free PMC article.
Review.
Tumor Microenvironment as A "Game Changer" in Cancer Radiotherapy.
Magdalena Jarosz-Biej, Ryszard Smolarczyk, Tomasz Cichoń, Natalia Kułach.
Int J Mol Sci, 2019 Jul 03; 20(13). PMID: 31261963    Free PMC article.
Highly Cited. Review.
Efficacy of Local Treatments for Hepatocellular Carcinoma Involving the Inferior Vena Cava and/or Right Atrium.
Han Ah Lee, Chai Hong Rim.
J Hepatocell Carcinoma, 2020 Dec 31; 7. PMID: 33376712    Free PMC article.
Review.
Radiation-induced abscopal effect and its enhancement by programmed cell death 1 blockade in the hepatocellular carcinoma: A murine model study.
Gyu Sang Yoo, Won-Gyun Ahn, +3 authors, Hee Chul Park.
Clin Mol Hepatol, 2020 Dec 08; 27(1). PMID: 33280350    Free PMC article.
PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+ T cell-dependent antitumor immunity and abscopal effect after local irradiation.
Yi Na Yoon, Eunju Lee, +3 authors, Jae-Sung Kim.
J Immunother Cancer, 2022 Mar 16; 10(3). PMID: 35288465    Free PMC article.