The Effects of Localized Radiation Therapy on Systemic Tumor Progression in Cancer Patients

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Abstract

Radiation therapy may promote cancer metastasis by a variety of mechanisms, including induction of epithelial-mesenchymal transition (EMT) as well as upregulation of biomarkers associated with a more metastatic phenotype. However, radiation therapy can also induce systemic immune responses within the body, resulting in local and metastasized tumor burden reduction through a phenomenon known as the abscopal effect. New radiotherapy modalities and improving technology has also expanded the possibilities of radiotherapy in the context of immunomodulation. This review discusses the effects of radiotherapy beyond acute cell death of the irradiated cells and their implications for cancer patients.

Introduction

The primary purpose of radiation therapy is to damage the DNA within cancer cells, causing replication errors, and ultimately cell death1. Concentrating the radiation to solely the tumor is challenging, however, and healthy cells in the surrounding tissue are often subjected to damage as well. Moreover, if the cancerous cells receive a sublethal dose of radiation, they may be able to either repair their DNA or replicate despite the damage. In some cases, the mutations induced by sublethal doses of radiation may even drive tumor progression and cancer metastasis2.

Radiation Therapy and EMT

Radiation therapy has been linked to increased metastasis of cancer via a variety of mechanisms.
Numerous preclinical and clinical trials have reported the correlation between radiation therapy
administration and increased metastasis (in vivo) and metastatic behavior of cancer cells (in vitro). In an experiment by Rofstad et al., 2005, mice injected with human melanoma cells and exposed to radiation therapy had greater metastasis to the lungs by almost two-fold3. Further, in a trial by Strong et.al, patients with oro- and hypopharyngeal squamous cell carcinoma were randomly treated with either surgery or radiotherapy4. Results showed that patients treated with radiotherapy had more cases of distant metastasis, though an exact mechanism was not proposed.

Evidence from numerous in vivo and in vitro experiments indicate that radiotherapy within several cancers (breast, prostate, esophagus, lung, colorectum, uterine cervix, stomach, and glioma), can promote EMT5. EMT is a process by which epithelial cells acquire mesenchymal phenotypes, including enhanced migratory capacity and the ability to self-renew, or divide into two identical daughter cells. Normal adult mesenchymal cells include stromal stem cells, typically found in the umbilical cord, bone marrow, and adipose tissue. In cancer, however, EMT can produce cells displaying mesenchymal phenotypes that are highly migratory, invasive, and resistant to apoptosis, thus more capable of metastasizing to distant sites67. In addition, EMT has been linked to the production of cancer stem cells, a subpopulation of cancer cells known for their ability to self-renew8. Thus, while an important physiological process, the EMT is typically viewed as deleterious in the context of cancer. In A549 lung cancer cells, radiotherapy has been shown to directly promote EMT via increased levels of TGF-\beta, a cytokine known to drive the process9. Furthermore, lower E-cadherin levels, a marker of epithelial cells, as well as higher vimentin levels, a marker of mesenchymal cells, were also reported, thus strongly indicating radiation-induced EMT in the A549 cell line. Additionally, irradiation has also been shown to cause upregulation of integrin, MMP9, and MMP2, all of which are known drivers of EMT10. Figure 1 displays the upregulation of TGF-\beta, MMPs, Vimentin, and the downregulation of E-cadherin that are all involved in the EMT process11.
consequence of Wnt/\beta Catenin activation. This data collectively suggests a decrease in E-cadherin expression in cancer induced by radiation, which could have potential clinical relevance for cancer patients considering the correlation between E-cadherin expression and prognosis in the disease.

Figure 1 |  Epithelial-mesenchymal transition and its Biomarkers12

Radiation Therapy and the Abscopal Effect + Role of Immune System

The well-established phenomenon known as the abscopal effect convolutes the story of the systemic effect of localized radiation therapy on cancer progression. Multiple studies have shown that localized radiotherapy can cause tumor reduction in both local and metastasized regions, though complete elimination of all tumor sites following localized radiation therapy is rare5. The putative mechanism by which the abscopal effect works is the generation of a systemic anti-tumor immune response. This was confirmed by Demaria’s 2004 experiment that depicted the abscopal effect as an immune system dependent process, as immunodeficient mice did not exhibit systemic tumor regression13. When irradiated cells die and discard their contents, immune cells are able to recognize and mount a response against the antigens which are presumably present in cancer cells in distant metastases. This drives an
immune response throughout the body, targeting areas of metastasis as well.

Figure 2 |  The Abscopal Effect14

Numerous studies have explored the abscopal effect as a possible treatment for cancer and cancer
Metastasis15. It has been revealed that surgery combined with radiotherapy has had no effect on the rate of abscopal effect in patients, and neither does the dose of radiation or treatment location (local or metastasized). However, the combination of radiation therapy and immunotherapy has produced interesting and potentially promising results in recent years16.

Combination Therapies

Drug resistance has become a pertinent issue for patients, as tumor cells evolve and develop immunity to certain forms of treatment17. Therefore, combination therapies have been devised to help address these concerns.

Checkpoint-inhibitor therapy is a form of immunotherapy that prevents the binding of checkpoint proteins like PD-1, presented on the surface of immune cells, to their partner proteins, like PD-L1, which are often overexpressed on the surface of cancer cells18. This promotes T-cell and NK cell cytotoxic effects within the immune-suppressive tumor microenvironment. The effectiveness of immunotherapy has created potential combinatorial roles of the treatment with radiotherapy, allowing for increased efficacy in preventing recurrence of cancer through the elimination of immune tolerant tumor cells. Several clinical trials have shown that checkpoint- inhibitor therapy and radiation therapy displays a mutualistic relationship, promoting the abscopal effect in combination5. In an experiment by Golden et.al, 41 patients with at least three sites of metastatic cancer were treated with 35 Gy of radiotherapy (10 daily fractions) to one of the sites in combination with immunotherapy over the course of two weeks. 27% of enrolled patients experienced an abscopal response19.

Novel Radiotherapy Modalities

‘Irradiation has been the primary form of cancer treatment, however new research has found that immunosuppressive factors increase prevention of recurrence and metastasis. These treatment may be able to address the concerns laid out in this paper regarding external beam radiotherapy as a potential threat of cancer metastasis.Immunomodulation has been a theoretical pathway for more effective cancer treatment, and novel treatments such as Volumetric Modulated Arc Therapy (VMAT), Spatially Fractionated Radiotherapy (SFRT), and ultrahigh dose rate FLASH irradiation (FLASH) have shown promise.

Volumetric Modulated Arc Therapy (VMAT)

VMAT is a form of radiotherapy that involves 360^{\circ} beam radiation. The novel therapy allows for continuous dosage delivery as the machine rotates20. By using constant rotation, VMAT allows for irradiation to the tumor at several different angles thus lowering damage to surrounding tissue and minimizing organ damage21. Despite VMAT lacking clinical data due to its recency, multiple studies have displayed its effectiveness.

VMAT is commonly compared to IMRT, which utilizes multiple beams to target a tumor using computer algorithms. The difference is that VMAT rotates in an arc whereas IMRT does not22. This new arc technique has been found to be much more effective than IMRT, displaying its ongoing effectiveness. VMAT was found to reduce treatment times in comparison to IMRT. In addition, it has been found to be more effective at rectal sparing in prostate cancer, bladder sparing in gynecological cancer, and lung sparing in lung cancer23.

One of the biggest limitations of VMAT is that it exposes nearby tissue to low doses. This may cause secondary malignancies. According to estimates, the risk may increase by 1-2% in patients that survive 10 years after treatment24.

Spatially Fractionated Radiotherapy (SFRT)

SFRT, usually administered through a process named GRID therapy, is a form of treatment normally performed on larger malignant tumors. It uses a non-uniform dose, administering high beams of radiation while also minimizing radiation induced toxicity. SFRT has been used for a century now, however expanding technology and knowledge has allowed for promising use within the context of immunomodulation.

In the past, 2D grids have been used to treat patients, commonly resulting in favorable oncological outcomes25,26. Newer 3D LATTICE radiotherapy (LTR) has displayed even greater outcomes on patients with larger tumors including no added toxicity and greater local control27. Amendola et al have used LRT on patients with pelvic and chest cancer, being able to greatly reduce tumor volume and increase survival length, despite several patients being deemed terminally ill28.

SFRT in conjunction with other forms of radiotherapy has also shown to have great benefits. Stereotactic body radiation therapy (SBRT), a form of therapy involving machines for more accurate radiation delivery, has shown to increase control rates in lung cancer patients29.

Figure 3 | Dose calculations for Spatially fractionated radiotherapy using GRID therapy30

Ultrahigh Dose Rate FLASH Irradiation (FLASH)

A limitation to radiotherapy is the ability to provide high doses. Through general external-beam radiation, there is a limit to the dose of radiation one can receive, typically because high doses may result in radiation-induced toxicities to nearby tissue. This limits the extent to which tumors can be cured and treated. FLASH therapy is a process in which ultra-high doses (around 50-70 gy) are given to patients31. Pre-clinical trials have displayed that this ultra-high dose rate can actually minimize radiation induced toxicities while also maintaining the same curative effect of radiotherapy.

However, this is counter-intuitive as high doses can result in toxicities to nearby tissue. What makes FLASH unique is that it is given in parts of a second compared to the few minutes that conventional external-beam radiation therapy takes. This allows for greater irradiation output while also minimizing damage to nearby tissue32. In vitro studies have also revealed that these pulses of radiation are more stable than continuous standard forms of irradiation33.

In an experiment by Favuadon et al, researchers compared conventional and FLASH irradiation towards mice. Mice exposed to 15gy experience TGF-beta induced pulmonary fibrosis, a cytokine also known to promote EMT. However, mice exposed to 20 gy irradiation using FLASH treatment experienced significantly fewer cases of pulmonary fibrosis33.

However, it is important to note that there have been several studies showing no benefit of using FLASH irradiation of conventional forms. Smyth et al. performed high doses of FLASH on mice and standard doses through conventional forms and found no statistically significant difference between the dose toxicity values (TD50)34.

Discussion

Radiation therapy is one of the most employed forms of cancer treatment, with almost half of all cancer patients undergoing the procedure throughout their treatment process. There are two major observations reported regarding the effect of localized radiation treatment on the systemic progression of cancer. The first is that radiation therapy can drive the formation of distant metastases through mechanisms including induction of EMT. The second, in stark contrast to the progression of metastasis, is that localized radiation therapy can exert a systemic tumor-suppressive effect on non-irradiated distant metastases through the stimulation of a systemic immune response, a phenomenon termed the abscopal effect. Both claims have significant evidence to support them, and require deeper research to understand their exact mechanisms and uses. Though the abscopal effect may in some instances facilitate systemic tumor degradation and, combined with immunotherapy, represent a viable treatment path, radiation therapy alone may pose a risk of driving metastasis, despite local tumor burden reduction.

The primary mechanism thought to drive the abscopal effect is the generation of a systemic immune response which can exert an effect on non-irradiated lesions. However, radiation therapy has also been shown to increase TGF-\beta secretion. TGF-\beta is known to be immunosuppressive, acting through the inhibition of T cell proliferation, and therefore may impair the mounting of a systemic abscopal response35,36. Further, studies have shown that in vitro, TGF-\beta impedes DC maturation and differentiation. As displayed in , T cells rely on neoantigens (proteins embedded on cancer cells with tumor mutations) presented to them by dendritic cells (DCs) to form an immune response37 Hence, the induction of TGF-\beta secretion driven by radiation therapy may result in the inhibition of the T-cell stimulation which is imperative to inducing the abscopal effect38. To combat TGF-\beta’s immunosuppression traits, scientists have conducted experiments combining radiotherapy with TGF-\beta neutralization and found that it drastically increases T-cell responses to tumor antigens throughout the body39. Further studies have shown that this may even develop into a viable treatment option for patients, however further research and trials are necessary.

Figure 4 | Toll-like receptor 4 & 5′ adenosine monophosphate-activated protein kinase; Interferons Signaling40

Furthermore , E-cadherin is known to play a role in regulating the release of cytokines and chemokines40. Therefore, when downregulated, as has been shown in irradiated cells, this role is also lost and the induction of an immune response against tumor cells may be impaired. In contrast, however, other studies have shown that radiotherapy can increase DC maturation and presentation of neoantigens through the downregulation of E-cadherin. As shown in figure 4, HMGB1 plays an important role in DC maturation, acting via the TLR4 pathway. Studies suggest that a decrease in E-cadherin can result in an increase in HMGB1 production, driving DC maturation41. Therefore, as radiotherapy has been shown to cause a downregulation of E-cadherin, it can be speculated that radiotherapy can promote an abscopal response in some contexts.

Studies have indicated radiotherapy alone is often insufficient to trigger an effective systemic immune response on its own. As shown before, it is only when combined with checkpoint-inhibitor therapy that the anti-tumor response within the body becomes effective42. This evidence suggests that radiation therapy may not be able to stimulate the abscopal effect to a significant degree.

In conclusion, there is a vast collection of studies highlighting both radiotherapy metastasis-inducing effects as well as its ability to prompt the abscopal effect in some contexts. Both claims have extensive research to back them up, and are not necessarily mutually exclusive. Both phenomena display radiation therapy’s ability to manipulate the immune system and cause a change within the body, whether it be metastasis or an abscopal response. However, at this moment there is a wider variety of evidence indicating radiotherapy’s ability to promote distant tumor cell migration in cancer through the EMT. Biomarkers of metastasis such as MMPs, Vimentin, TGF- Beta, and integrins were all shown to be upregulated during radiotherapy, further suggesting its role in promoting metastasis. In addition, along with the inability of radiation therapy alone to promote an abscopal response in many instances, there are other contradictory studies suggesting that radiotherapy can, in fact, block the abscopal effect. Novel radiotherapy modalities and combination therapies have been explored as potential ways to maximize the benefits of radiotherapy while minimizing the risks of recurrence and metastasis. At present, radiotherapy is considered a standard treatment for cancer, however patients may be wary of the possibility of metastasis and recurrence. Expanding technology and novel treatment methods are helping to combat these risks, however more clinical trials and experiments must be pursued.

Materials & Methods

All materials were obtained through public research papers and data published online. Research papers were selected on their relevance, recency, and credibility to the topic of the paper. Datasets include data from patient prognosis, biomarkers for metastasis, and more.

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