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CCR Translations Clinical

Implications of the Bystander and Abscopal
Effects of Radiation Therapy
Vivek Verma1 and Steven H. Lin2

Siva and colleagues have demonstrated that localized thoracic tant clinical implications of these data, especially in the era of
radiation resulted in DNA damage at out-of-eld sites. Although immune therapies. Clin Cancer Res; 22(19); 47635. 2016 AACR.
these interesting ndings require validation, we discuss the impor- See related article by Siva et al., p. 4817

In this issue of Clinical Cancer Research, Siva and colleagues cells could be seen in the vicinity of the hair follicle. miRNA and
describe evidence of DNA damage to not only peripheral blood exosomal signaling may also be involved, although the authors
lymphocytes coursing through the irradiated thorax, but sus- could not nd evidence to support the latter. It is known that
tained DNA damage repair as showed by gH2AX foci within certain inammatory cytokines can mediate DNA damage
eyebrow hair follicles far outside of the irradiated area (1). Several response through elicitation of nitric oxide (NO) generation by
cytokines are implicated to at least partially mediate these appar- inducible NO synthase (iNOS; ref. 4). Interestingly, iNOS is an
ent bystander effects. Although the nding is an elegant portrayal enzyme induced in activated monocytes and macrophages, and
of this phenomenon, it may have profound implications for both the authors discovered that CCL3 was signicantly upregulated at
normal tissue toxicity prevention and cancer therapy. 4 weeks that was dose independent, much like the gH2Ax foci in
Cases of the out-of-eld "systemic effects" of radiotherapy the hair follicles. It is known that CCL3 and iNOS are coexpressed
exerting tumoricidal control at distant sites, known as the "absco- in activated macrophages, and CCL3 plays a role in inammatory
pal phenomena," have been sporadically described for decades responses through binding CCR1 and 5 in mediating radiation-
(2) and are likely contributed by complex interactions of the induced lung injury (5). Whether this is the mechanism mediating
immune system with localized inammation induced by radio- this response in distal sites in the hair follicles is uncertain;
therapy, including through both T-cell and cytokine signaling (3). possible future studies could explore the role of activated macro-
The proposed mechanisms, likely similar to what is responsible phages or iNOS expression in distant unirradiated areas.
for the bystander effect on normal tissue, are likely overly sim- Although it is known that an intact immune system is impor-
plistic (Fig. 1) but generally involve local tumor ablation, antigen tant for radiation-killing effect on tumors (6), it could very well be
presentation, and inammatory mediators. The resultant systemic that indirect damage to normal tissues by the immunologic and
effect may produce generalized symptoms that patients often inammatory response may manifest as "silent" toxicities that
experience during protracted course of radiotherapy (e.g., fatigue, could result in an increased risk of secondary malignancy in the
anorexia). In the current study (1), it is still uncertain how DNA appropriate patient populations, as the level of inammation
damage as measured by gH2Ax foci in hair follicle cells is gen- produced could be related to genetic susceptibility of individuals.
erated. However, unlike peripheral blood lymphocytes (PBL), We acknowledge that it may be questionable that such small
which developed measurable gH2Ax foci at 1 hour that mostly numerical increases in DNA damage foci may portend to clinically
disappears at 24 hours, eyebrow hair follicle cells developed DNA evident increase in toxicity or radiation-induced neoplasms, espe-
damage starting at 24 hours after the rst fraction, and persisted cially with the 3-month time course as seen in the data. However,
even 4 weeks into radiotherapy and nearly recovered to basal the "silent" toxicities experienced by highly radiation-sensitive
levels by 3 months after radiotherapy. The initial delay and tissues, such as the bone marrow and gonads, may very well have
sustained time course suggests systemic inammatory effects stochastic and long-term implications. Inammatory mediators
possibly mediated in part by cytokines and/or inammatory cells may modify gene expression via transcriptional and/or epigenetic
gathering at distant sites away from the irradiated zones, although mechanisms. Importantly, these alterations can occur in
the authors did not comment on whether these inammatory "bystander" germ cells, potentially creating a major conduit for
predisposition of radiation-induced malignancies in future gen-
erations (7).
Department of Radiation Oncology, University of Nebraska Medical The most logical extension to the current work is to ask the
Center, Omaha, Nebraska. 2Department of Radiation Oncology, Uni- question to what extent, similar DNA damage occurs in other
versity of Texas M.D. Anderson Cancer Center, Houston, Texas. locations and organs. Radiation modality, tumor histology and
Corresponding Author: Steven H. Lin, Department of Radiation Oncology, The volume, location, timing of immunotherapy with radiotherapy,
University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 97, and the patient's immune microenvironment may play a role,
Houston, TX 77030. Phone: 713-563-8490; Fax: 713-563-2366; E-mail:
among numerous other factors (8). Furthermore, it has been
recently reported using mathematical modeling that different
doi: 10.1158/1078-0432.CCR-16-1512 tumor locations may be more "immunogenic" than others (9).
2016 American Association for Cancer Research. The model encompasses several factors, not limited to physiologic 4763
Verma and Lin

DNA damage to DNA damage to

distant tumor cells bystander cells

+ ce
D8 Systemic
f C propagation
o no
Radiation ati
Ac Production of

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Ce of tumoricidal
immune response
Elicit inflammatory

Cancer cell

2016 American Association for Cancer Research

Figure 1.
Simplied mechanism of how local radiation may induce a bystander or abscopal effect to cause DNA damage at distal sites. Radiation induces a number of changes
during the cell-killing process that can elicit a number of inammatory mediators from the dying cancer cell that either attract or activate immune-related
cells with the tumor microenvironment. These cells can generate additional cytokines that act locally and circulate systemically or propagate either hematogenously
or lymphatically to act on normal tissues and tumor cells located at distant sites apart from the irradiated primary tumor. DCs, dendritic cells.

blood ow and imprinting of T cells by antigen-presenting cells. tent detection of the abscopal phenomenon to date, in 11 of 41
Despite the virtual nature of the work, the prominent theme (27%) prospectively treated patients with various metastatic
remains that factors increasing T-cell trafcking to metastatic sites cancers (12). One of at least three actively metastatic lesions was
may be most associated with likelihood of observing an induced irradiated (35 Gy/10 fractions), and granulocyte macrophage
abscopal response. Similarly, it remains to be deduced whether colonystimulating factor (GM-CSF) was coadministered. GM-
particular "bystander" sites have greater proclivities to receive CSF by itself is not expected to generate any tumor response;
DNA damage from inammatory mediators. Moreover, studies however, the median survival of patients demonstrating an absco-
have shown that these phenomena may occur with large, ablative pal response (dened as 30% size reduction) experienced nearly
doses (10); albeit in different treatment conditions, others have 3-fold increased survival (21 vs. 8 months). This is a strong
not validated this notion (11). Although many tumors are radio- rationale to use when similar approaches are being considered
therapeutically treated using hypofractionated regimens, it would for oligometastatic cancers, as well as high-risk nonmetastatic
be of great importance to assess whether these regimens produce cancers, to enhance "cures." However, we must proceed cautious-
altered levels of postirradiation inammation as compared with ly, as immune activation that works great for the abscopal effect
conventional fractionation. will likely also exacerbate the bystander effect, to exert degrees of
Furthermore, the exploding eld of immunotherapies has systemic normal tissue toxicities beyond what immunotherapies
generated feverish interests in whether abscopal responses could are causing by themselves.
be harnessed for cancer therapy, with ever burgeoning numbers of In summary, Siva and colleagues have demonstrated the radi-
combination radiationimmunotherapy trials. The historically ation bystander phenomenon manifested as persistent DNA
unreliability of a "systemic anti-cancer effect of radiotherapy" damage foci in the hair follicles well outside the irradiated zone
appears to be more reproducible with the combination of immu- in the thorax. Although this may be understood as the end result
notherapies, such as the immune checkpoint inhibitors. A sem- of the systemic inammation that is induced by localized radio-
inal study by Golden and colleagues illustrated the most consis- therapy, much needs to be learned about the mechanism and

4764 Clin Cancer Res; 22(19) October 1, 2016 Clinical Cancer Research
Bystander and Abscopal Effects of Radiotherapy

long-term consequence of this effect. The current study is a Authors' Contributions

demonstration that systemic normal tissue injury likely occurs Conception and design: S.H. Lin
alongside the "abscopal effect," with ablative radiotherapy as the Development of methodology: S.H. Lin
"re starter" in the presence of cancer immunotherapies. The Acquisition of data (provided animals, acquired and managed patients,
provided facilities, etc.): V. Verma, S.H. Lin
clinical implications of this interesting work for both oncogenic Analysis and interpretation of data (e.g., statistical analysis, biostatistics,
treatments and normal tissue toxicities, especially in this era of computational analysis): V. Verma, S.H. Lin
immune-stimulation therapies, cannot be overstated. Writing, review, and/or revision of the manuscript: V. Verma, S.H. Lin
Administrative, technical, or material support (i.e., reporting or organizing
Disclosure of Potential Conicts of Interest data, constructing databases): S.H. Lin
S.H. Lin is a consultant/advisory board member for AstraZeneca, ProCure, Study supervision: S.H. Lin
and US Oncology and reports receiving commercial research grants from Elekta,
Peregrine Pharmaceuticals, Roche/Genentech, and STCube Pharmaceuticals. Received July 8, 2016; accepted July 13, 2016; published OnlineFirst July 25,
No potential conicts of interest were disclosed by the other author. 2016.

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