Combination with Stereotactic Body Radiotherapy Offers a Promising Strategy to Overcome Resistance to Immunotherapy in Advanced Renal Cell Cancer

Immunotherapy for renal cell cancer (RCC) has witnessed several developments for more than two decades. Checkpoint inhibitors, including anti-CTLA-4 and anti-PD-1/PD-L1 blockers, have changed the treatment landscape for patients with advanced RCC in the past 3 years. Despite these advances, more than 55% RCC patients become resistant to different immunotherapies without other treatment combination. Among various attempts at overcoming resistance to immunotherapy, stereotactic body radiotherapy (SBRT) has been found to potentiate the activity of immunotherapy agents through several potential mechanisms, including normalization of microvessels to alleviate tumor hypoxia, improvement in efficient delivery of drugs, abundant neoantigen exposure, and recruitment of antitumor immune cells to alter the immunosuppressive tumor microenvironment. Preclinical studies and clinical case reports have predicted that the combination of SBRT, an immunotherapy, may lead to remarkable results. This review aims to provide the biological basis for the feasibility of combining SBRT to overcome immunotherapy resistance and to review the currently available clinical evidence of this combination therapy in patients with advanced RCC.


Introduction
Renal cell cancer (RCC) is the third most common urological carcinoma, and over 90% cases of RCC in adults is clear cell in histology [1,2]. e prognosis of RCC cases depends on the disease stage, tumor properties, the state of tumor metastasis, accurate diagnosis, proper treatment, and so on [2]. Advance and metastatic cases still carry a poor prognosis with a 5-year survival of about 9-12% [3]. Furthermore, nearly 30% of RCC cases with early-stage diagnosis will suffer from recurrence and progression after surgical procedures partly because of pre-existing micrometastatic loci before the surgery or some uncertain reasons [4]. erapeutic options for advanced RCC patients should be based on histology (clear cell or not clear cell) and the most widely used prognostic factor model is from the Memorial Sloan Kettering Cancer Center (MSKCC) with stratification in three prognostic categories (favorable, intermediate, and poor risk) [5]. Prognostic factors for multivariable analysis included five variables-Karnofsky performance status (KPS) less than 80%, interval from diagnosis to treatment of less than 1 year, serum lactate dehydrogenase (LDH) greater than 1.5 times the upper limit of normal (ULN), corrected serum calcium greater than the ULN, and serum hemoglobin less than the lower limit of normal (LLN). Patients with none of these risk factors are considered low risk or with good prognosis, those with one or two factors present are considered intermediate risk, and patients with three or more of the factors are considered poor risk. First-generation systemic therapy, comprising cytokinebased procedures including interferon-alpha (IFN-α) and interleukin-2(IL-2), is recommended for advanced RCC patients since there is documented evidence for its effectiveness against advanced RCC. Targeted therapies including tyrosine kinase (TKI) and mTOR inhibitors, and antibodies against vascular endothelial factor (VEGF) and platelet-derived growth factor (PDGF), have tremendously improved clinical outcomes compared with cytokine therapy alone.
Development and progression of advanced RCC have been slowed or even arrested through immune checkpoint inhibitor (ICI) combination therapy (ipilimumab plus nivolumab), which, in patients with intermediate or poor risk, showed a better overall survival (OS) than VEGF target therapy recently [6]. However, the objective response rate (ORR) is 42% in ICI combination therapy suggesting that most RCC patients are resistant to ICI combination therapy [6]. e lack of predictive biomarkers of high quality has resulted in missed treatment opportunities for RCC patients who could not benefit from ICI therapy. erefore, it is crucial that RCC patients overcome resistance to treatment and to expand applicable people who could benefit from ICI therapies.
ough RCC was considered to be resistant to radiotherapy, this concept is being challenged, particularly in the past decade, due to the continuous advances and innovation in radiotherapy technology. Increased doses of radiotherapy to tumor lesions has been observed following significant improvement in the accuracy of radiotherapy, which achieved better control of the damage in surrounding normal tissue. Stereotactic body radiotherapy (SBRT), which comprises high doses of radiation delivered in fractions (usually ≤5), has evolved to become an important treatment strategy for both primary lesions and metastatic diseases in different organs for RCC patients. Several key biological pathways triggered by SBRT prime the system immune to eliminate tumor cells. erefore, SBRT and immunotherapy display synergistic effects, which are reviewed in this study to determine the biological basis and current preclinical and clinical evidence for combination treatment of SBRT and immunotherapy.

Current Immunotherapy in Clinical Trials for Patients with Advanced RCC
Currently, five immunotherapy agents, IL2, IFN-α, ipilimumab, nivolumab, and pembrolizumab, have been approved for treating advanced RCC, either alone or in combination with other drugs. Current immunotherapies for patients with advanced clear cell or non-clear cell RCC are described in Table 1. IL-2 and IFN-α are reported to achieve durable complete or partial response in only a small population of patients [9,17]. For the majority, the benefit from cytokine-based therapy is limited and the trials to improve the effectiveness have met with efficacy uncertainties. High-dose IL-2 showed substantial toxicity in patients [18]. us, selection of patients treated with high-dose IL-2 mainly depends on safety and the tumor histology (clear cell approved), medical comorbidities, patient's performance status, risk scores, and the patient's attitude to treatment risk.
IFN-α plus VEGF-targeted therapies such as bevacizumab may improve the prognosis of RCC to a certain degree [10,11], but whether toxicity was greater in the combination therapy arm remains controversial. However, IFN-α alone was inferior compared to the sorafenib (VEGF TKI) [12] or temsirolimus (mTOR inhibitor) monotherapy [13].
ere is controversy over ICI combination therapy in previously untreated favorable-risk patients. Also, the study population in CheckMate 214 included favorable-risk patients treated with ICI combination (N � 125) or sunitinib (N � 124) [6]. Exploratory analyses of 18-month OS rate found that the favorable-risk patients benefited more from sunitinib (88% vs. 93%). e ORR (29% and 52%; p < 0.001) and median progression-free survival (PFS) (14.3 months vs 25.1 months; HR: 2.18; p < 0.001) were lower in favorable-risk patients taking ICI combination than sunitinib in this trial. However, the CR rates were 11% and 6% for the ICI combination and sunitinib groups, respectively. Conversely, a phase I trial (CheckMate 016) supported the use of ICI combination in patients at any risk with confirmed advanced clear cell RCC, including those who received prior therapy [14]. e study included patients with poor (N � 6), intermediate (N � 47), or favorable (N � 47) risks. Patients with favorable risk comprised 44.7% of those taking ICI combination. e data for the favorable-risk patients alone were not published, but the 2year OS for the entire cohort was 67.3%. e confirmed ORR for the cohort was similar in both arms (40.4%) [14]. Because of these conflicting results, the FDA approval for nivolumab plus ipilimumab only included patients with intermediate-or poor-risk RCC for first-line therapy.
In another randomized phase III clinical trial (Check-Mate 025), patients (N � 821) with previously treated (excluding mTOR inhibitors) advanced clear cell RCC were assigned to receive nivolumab or everolimus (a mTOR   2 Journal of Oncology inhibitor).
A retrospective analysis of 35 patients with metastatic, non-clear cell RCC who received at least one dose of nivolumab showed that 20% of patients had partial response and 29% of patients had stable disease in 8.5 months median follow-up and 3.5 months median PFS [19]. McKay et al. found that of 43 patients with metastatic, non-clear cell RCC,8 (19%) patients had modest responses to PD-1/PD-L1 and 4 (13%) patients who received PD-1/PD-L1 monotherapy showed an objective response [20].
In general, the next generation of immunotherapies (ICI: ipilimumab, nivolumab, and pembrolizumab) raised hopes for patients with advanced RCC. From the results reported

Not reached in both arms
Rini et al. [16] so far, clear cell RCC and intermediate-risk/poor-risk populations could benefit more than others. ICI therapies showed the potential of improving the ORR and PFS with or without anti-VEGF therapy, which also resulted with lower severe toxicities than high-dose IL2. However, the OS benefit of pembrolizumab plus axitinib over sunitinib remains unknown. Considerable efforts are nevertheless needed to reduce the resistance rate to immunotherapy and improve its efficiency.

Potential Mechanisms of Adding SBRT to
Overcome the Resistance to Immunotherapy ere are several underlying mechanisms explaining how SBRT enhances immunotherapy efficacy in the tumor microvasculature as depicted in Figure 1.

Tumor Microvasculature Response to SBRT.
Folkman hypothesized that the most common pathway for new microvessel development in malignant tumor is angiogenesis [21]. In physiological conditions, pro-and antiangiogenic factors maintain a dynamic balance for the normal development of blood vessels. However, in malignant tumors, this balance is perturbed by hypoxia. Excessive proangiogenic factors promote abnormal growth of microvessel, which become disorganized and form tortuous, dilated, hyperpermeable, and dysfunctional microvessels, resulting in intensifying hypoxia and poor transportation efficiency within the tumor microenvironment. ese abnormal microvessels impede immune cell migration, function, and transportation of therapeutics. e response of microvessels to SBRT, their normalization structure, and endothelial cell (EC) apoptosis determine the radiosensitivity of certain malignant tumors, including RCC. EC apoptosis might be particularly crucial for RCC because of its extensive microvasculature.
In 2003, Garcia-Barros and colleagues discovered that high-dose SBRT (more than 8-11 Gy) facilitates apoptosis of EC in a dose-dependent manner and normalizes tumor microvasculature [22]. More than 8-11 Gy radiation induced EC apoptosis, and single dose of 15-20 Gy radiation resulted in rapid EC apoptosis. With a single dose of 15 Gy, EC apoptosis, involving acid sphingomyelinase (ASMase), is initiated in one hour, reaches its peak in four hours, and ceases in six hours. ASMase hydrolyses sphingomyelin, a proapoptotic messenger that coordinates transmembrane signaling of FAS-FASL-mediated and tumor necrosis factor-(TNF-) receptor-mediated apoptosis and DR5-TRAIL-mediated apoptosis through death-inducing signaling complexes within seconds after irradiation and without DNA damage. Clustering of receptor-bearing rafts facilitates the stimulation of receptor-mediated apoptosis. Exclusion of survival-regulating proteins and growth factors from these clustered rafts might cause EC apoptosis. A previous study showed that ASMase − /− mice had double the growth rate of MCA129 fibrosarcoma and half the rate of EC apoptosis than ASMase +/+ mice [22], suggesting that EC apoptosis plays an important role in tumor cell death. Sathishkumar et al. observed that patients having a complete or partial response after SBRT (15 Gy/1f ) had substantially augmented or higher levels of a secretory form of ASMase (S-ASMase) activity before radiotherapy was given (high basal activity), while little-to-no increase in low basal activity was observed in nonresponders [23]. Furthermore, 60% of patients with clear-cell renal cancer are highly vascularized owing to transcriptional silencing (hypermethylation) or mutation of von Hippel-Lindau (VHL). Degradation of hypoxia-inducible factor-1 (HIF-1) requires pVHL, and deficiency in pVHL results in HIF-1 accumulation and angiogenesis.
Given that renal cancer is assumed to be sensitive to SBRT [24], it was found that EC damage appears to be induced by both SBRT and conventional fractionated radiation (CFRT). ese contrasting results may be due to the fact that EC apoptosis contributes significantly to tumor cell elimination in SBRT, and EC apoptosis was merely due to low-dose irradiation of CFRT which may not induce tumor cell death effectively, as death signaling in EC is repressed by activation of HIF-1 in tumor cells [25].
Apart from EC apoptosis, SBRT enhances involvement of pericytes in tumor microvessels, and the pericyte-covered microvessels were functional with an increase in perfusion, which could alleviate hypoxia and improve transportation efficacy [26].
us, there is a normalization of blood microvessels, offering a "window of opportunity" for immune-cell migration and transportation of therapeutics.

e Systemic Antitumor Effect of SBRT.
Basic biological and clinical research in tumor radiotherapy have revealed that local radiotherapy, especially SBRT, can induce systemic antitumor effect in tumor lesions beyond the radiated field, termed the abscopal effect, which has been reported in various malignancies including melanoma, lymphoma, neuroblastoma, and RCC and particularly in pulmonary metastases. A valid hypothesis explaining the mechanism behind abscopal effect is that high-dose radiation can cause tumor cells to die within a short period and expose new tumor antigens, so that radiated tumor cells function as natural tumor vaccines after radiation exposure [27][28][29]. Concurrently, during the process of tumor cell death, damage-associated molecular patterns, such as HMGB1, ATP, and heat shock proteins, are also released in large quantities. ese molecules can effectively induce dendritic cells (DCs) to recognize tumor-specific antigens resulting in their capture and migration of DCs to draining lymph nodes, where tumor antigens are presented to T cells [30], which in turn get activated and undergo massive proliferation. Activated effector T cells enter the circulatory system, recognize tumor cells far from the radiated field, and exert antitumor effects [31,32].
To explore whether SBRT can enhance the expression of tumor-associated antigens in patients with advanced RCC, Singh et al. studied the response to SBRT in patients with advanced RCC.

Efficacy of SBRT in Patients with Advanced RCC
Results from several studies support that SBRT differs from CFRT for RCC patients, and SBRT is effective at controlling both primary and metastatic lesions of RCC, as summarized in Table 2.

SBRT Differs from CFRT in Treating Patients with RCC.
In recent years, SBRT has been delivered to patients with advanced RCC, with results showing a slow but persistent shrinkage of the renal tumor after SBRT [50]. Compared with CFRT, in RCC with bone metastasis, the median time to symptom relief between SBRT and CFRT was similar, but the symptom control rates of SBRT were much higher than those of CFRT [35]. Furthermore, the authors of the study also showed that the biologically effective dose (BED) ≥80 Gy was significant for better clinical response and was predictive of local control [35]. Similar results were reported by Altoos et al. showing SBRT-mediated control of thoracic, abdominal, and soft tissue lesions in RCC, with predictive factors for better local control being BED ≥100 Gy and dose per fraction ≥9 Gy [36]. An analysis of radiographic and symptomatic RT responses in 27 consecutive RCC patients with 37 lung lesions found that rates of radiographic local control with SBRT were much higher than CFRT [37]. To explore the difference between SBRT and CFRT on spine metastases from RCC, a total of 110 patients (34 CFRT; 76 SBRT) were retrospectively analyzed [51]. e researchers found that both CFRT (20 Gy/5f ) and SBRT (15 Gy/1f ) provided effective relief of symptomatic spine metastases from RCC, whereas CFRT relieved pain faster, and pain relief with SBRT was more durable [51].

SBRT Is Effective in Controlling Primary Renal Lesions.
Results from several studies indicate that SBRT is effective in controlling primary renal lesions. For example, renal tumors treated with SBRT show significant reductions in growth rate and tumor size after radiation [52]. Furthermore, a prospective phase I trial suggested that SBRT might be an alternative to cytoreductive nephrectomy for inoperable patients with advanced RCC [39]. e median tumor size was increased 17.3% at 5.3 months, and the median OS was increased at 6.7 months [39]. Inadequate single doses (≤7 Gy) in this prospective study could be the reason for these moderate results. For asynchronous bilateral RCC    [42]. However, SBRT led to dose-dependent renal dysfunction at 1-and 2-years [42]. erefore, sparing functional kidney from high-dose irradiation regions might help reduce the risk of renal dysfunction. In this context, SBRT (48 Gy/3f ) was found to be effective for primary small renal tumors and results in a satisfactory local control rate [43].

SBRT Controls Intracranial and Extracranial Metastases in RCC.
At present, several early studies have demonstrated that SBRT has an inhibitory effect on RCC metastases, including intracranial and extracranial metastases.

Intracranial Metastases Controlled by Stereotactic
Radiosurgery (SRS). Brain metastasis (BM) usually indicates poor prognosis in patients with RCC. Whole brain radiation therapy (WBRT) is considered a standard treatment in patients with multiple (>5) BMs. However, WBRT (usually 2-3 Gy per fraction) has limited efficacy in patients with BM from radio-resistant tumors such as RCC and melanoma whose median survival is 2-4 months. Stereotactic radiosurgery (SRS) for BM from RCC has been regarded as an alternative to surgery and delivers high-dose radiation in no more than 3 fractions (usually only one fraction), but avoids the toxic effects of WBRT. Studies in this regard have shown local control in 24 of 32 renal patients with 52 metastases while 4 patients had local progression using SRS for brain metastases in patients, in which the median dose was 22.0 Gy (range, 12.8-24.0 Gy), and the median OS was 6.3 months (range, 0.4-100.4 months) [44]. To evaluate outcomes of SRS in 16 RCC patients with multiple (≥5) simultaneous BMs (99 lesions in total) treated with SRS showed OS after 6 months and 1 year to be 50% and 31%, respectively. e median OS was 7.1 months (range 1-21), and 91% patients were free from local failure [45]. Besides, it has been found that SRS dose >18 Gy was associated with improved survival in patients with RCC [53]. Using this dose (range 15-20 Gy), a study involving 81 patients treated with SRS for BM from melanoma or RCC showed actuarial OS rates at 6 months and 1 year of 55.4% and 30.2%, respectively, and one-year local control (LC) rate of 79.4% for RCC [46]. Another similar, but smaller, study involved BM from melanoma (N � 26) or RCC (N � 15) patients, which found the lack of statistical significant differences in OS between patients with RCC and melanoma (8.4 mo vs 5.0 mo, p � 0.11) [54]. e results of these studies indicated that the OS of patients with BM from RCC treated with SRS is about 6.3-8.4 months, which is much longer than patients who underwent WBRT. e lack of high-grade evidence in current retrospective studies warrants the need for prospective studies in order to guide clinical practice, with the inclusion of more numbers of BMs to make valid conclusions.

Extracranial Metastases Controlled by Stereotactic Radiosurgery (SRS).
e ability of SBRT to control extracranial metastases in RCC was demonstrated in recent studies on 84 patients with 175 metastatic extracranial lesions who received SBRT (40-60 Gy/5f or 30-54 Gy/3f or 20-40 Gy/1f ); the 1-year local control (LC) rate after SBRT was 91.2%, and one factor of local failure was BED <115 Gy [48]. Another retrospective study of 48 patients treated for 70 spine metastases showed that the spine recurrence rates of 60% were mainly associated with salvage SBRT, which was only 20% for upfront SBRT. e study suggested that an early SBRT with higher doses could be more effective than salvage SBRT [49]. As mentioned above, SBRT effectively relieves symptomatic spine metastases in RCC. Compared with CFRT, SBRT trends to produce more durable pain relief [51], as demonstrated in 57 RCC patients (88 treatment) with spine metastasis, wherein Balagamwala et al. found that a single fraction SBRT achieved a median survival of 8.3 months and relieved pain rapidly with a median duration of 5.4 months of pain relief [38]. e currently available evidence reviewed in this study suggests that SBRT alone is effective for RCC, including primary lesions treatment and intracranial and extracranial metastases control; especially, patients with multiple intracranial metastases face poor prognosis. Single dose <7 Gy Journal of Oncology might be ineffective to achieve satisfactory treatment results in RCC patients, but higher dose radiation in SBRT monotherapy exerted robust disease control with acceptable clinical risk.

Preclinical and Clinical Evidence for the Inclusion of SBRT to Overcome
Resistance to Immunotherapy

Preclinical
Evidence. e introduction of ICIs, initially with anti-CTLA-4 antibodies, initiated a revolution in oncology. e inclusion of radiotherapy to ICI, animal models, or clinical studies focusing on the integrating radiation and related drugs followed in an attempt to find effect of radiotherapy on immune activation in several solid tumors [55]. Under this strategy, combining radiation with immune-checkpoint blockade increased locoregional control of tumors [31,56]. Furthermore, combination of local radiation with anti-CTLA-4 and anti-PD-1/PD-L1 inhibitors increased systemic disease control mediated by the abscopal effect [57]. An increase in complete regression of the irradiated primary tumor and reduced size of nonirradiated tumors outside the radiation field were observed when SBRT was combined with PD-1 blockade in melanoma and RCC models [58]. is effect was not attributed to tumor histology or host genetic background, but as it was tumorspecific, the effect was potentiated by PD-1 blockade, an abscopal tumor-specific immune response induced by radiotherapy in nonirradiated tumors [58]. e abscopal effect was exerted only in a small proportion of patients who received anti-CTLA-4 combined with radiotherapy, leading to PD-1/PDL1-mediated resistance to ipilimumab [57]. Another study showed blockade of adaptive immune resistance mediated by anti-PD-1/PDL1 antibodies upon localized radiation with anti-CTLA-4 therapy. Furthermore, nonredundant immune mechanisms mediated the superior activity of radiation and dual immune checkpoint blockade [59].

Clinical Evidence.
Clinical evidence reporting combination of SBRT with immunotherapy in advanced RCC is scant. A phase-2 trial combining high-dose IL2 and SBRT in patients with metastatic RCC [60] showed that 1-3 lesion sites were treated with SBRT with a dose of 21-27 Gy for single fraction or 25-33 Gy for 3 fractions.
e primary endpoint of the study-response rate-was 40%, with 1 patient presenting CR and 3 patients showing PR. e median duration of overall response (including CR and PR) was 5 months, and median stable disease (SD) duration was 6 months. Addition of SBRT to IL-2 increased the response rate in metastatic RCC patients by about 2-folds compared with IL-2 alone. Two cases have reported the induction of abscopal effect when SBRT was combined with ICI therapy in advanced RCC patients. One case reported by Xie et al.
showed a systemic complete response to SBRT (32 Gy/4f ) and pembrolizumab (anti-PD-1 antibody) in a patient with metastatic RCC [61]. e metastatic lymph nodes in the left mediastinum were irradiated with a total of 32 Gy administered in four fractions on four consecutive days [61]. e second case was that of a 24-year-old male with advanced clear-cell RCC and bone, lung, and nodal metastases who received SBRT (27 Gy/3f ) to the sacrum metastatic mass and subsequent ipilimumab and nivolumab therapy [62]. e sacrum mass was obviously shrunk with the therapy and no radiological evidence for lung and nodal metastases was found more than 12 months after SBRT [62].
To determine the effect of combining SBRT with immunotherapy, we searched ClinicalTrials.gov for studies and identified 13 ongoing clinical trials (Table 3). e vast majority of these trials were phase-2 studies and combined ICIs and (or) high-dose IL2.

Discussion
Recently, a single-arm phase-2 trial, which combined SBRT and a PD-1 blocker (pembrolizumab), suggested PFS improvement without serious safety signals in patients with oligometastatic NSCLC [63]. Immunotherapy (especially ICI) offers hope for patients with advanced RCC, particularly when SBRT is offered in combination. High dose of radiation effectively results in abundant ECs apoptosis which aids in reducing and renormalizing microvessels in the tumor for better transportation of therapeutics and migration of immune cells. Furthermore, SBRT has the potential to prime the immune system by exposing a mass of tumor antigens after irradiation. We acknowledge that there is limited evidence regarding this hypothesis and additional clinical studies are needed. However, in our humble opinion, SBRT offers a promising strategy for overcoming the resistance to immunotherapy in advanced RCC. Nevertheless, limitation of the combined therapy exists as follows: First, there exists the possibility of severe treatmentrelated adverse events. High-dose IL2 itself has shown to induce substantial toxicity. Furthermore, ICI therapy-induced acute kidney injuries such as acute tubulointerstitial nephritis, acute interstitial nephritis, and increased blood creatinine or acute renal failure have been reported [64][65][66]. As mentioned previously, application of SBRT to renal primary lesions could lead to dose-dependent renal dysfunction. erefore, the combination of SBRT with PD-1/ PD-L1 inhibitors will probably increase therapy-associated severe adverse events. Moreover, the incidence of other common treatment-related adverse events such as hypothyroidism and hyperthyroidism, which were the most frequent endocrine immune-related adverse events for PD-1/PD-L1 inhibitor alone, must be considered [67].
Second, the dose, fractions, and targets of SBRT plan are crucial, whereas a single dose <8 Gy might be insufficient and a higher dose presents a higher risk, particularly when combined with immunotherapy. erefore, a dose-escalation study is warranted to maximize clinical efficacy with acceptable toxicities for prospective clinical trials. Encouraging results from preclinical and clinical studies support the synergistic effect of SBRT and ICI therapy against brain metastases from melanoma [68,69]. Marrow-derived suppressor cells (MDSC) and immunosuppressive B cells could impede the antitumor activity induced by SBRTand immune 8 Journal of Oncology therapy [70,71]. ese immunosuppressive cells and heterogeneity in tumor might be the reasons for low incidence of abscopal effect in the clinic. Brooks and Chang suggested that we should abandon single-site radiation and that radiotherapy could be delivered to all targetable disease sites to broaden the T-cell repertoire and maximize the activation of the immune response [72]. ird, an appropriate sequence of SBRT and immunotherapy should be planned with detailed consideration. Harris et al. reported that the highest antitumor immune response in the mouse model of prostate cancer was obtained by adding immunotherapy after 3-5 weeks of radiotherapy; however, there was no obvious antitumor immune response after the end of radiotherapy [73]. It has also been suggested that CTLA-4 antibodies should be used to deplete regulatory T cells prior to radiotherapy to obtain maximum immune effects [74].
Fourth, pembrolizumab plus axitinib have yielded outstanding results, suggesting the benefit of concurrent or sequential treatment with anti-VEGF therapy combined with SBRT and immunotherapy, especially for patients with multiple lesions, some of which may be unsuitable for SBRT. However, the potential toxicities of anti-VEGF therapy with SBRT and immunotherapy need more attention [75].
In conclusion, combination of SBRT with immunotherapy may unlock antitumor immune responses that have the potential of overcoming resistance to immunotherapy in patients with advanced RCC.

Conflicts of Interest
All the authors declare that there are no relevant conflicts of interest to disclose.

Authors' Contributions
Xiaowen SUN collected, reviewed the main literature, and wrote the manuscript. Lu GAN supplemented the literature and revised the manuscript. Jiaming LIU pointed out writing design and revised the manuscript. Runa A, Lingling GE, and Baoqing Chen put up with helpful comments on the manuscript. All authors read and approved the final manuscript.