Abscopal effect of stereotactic radiotherapy combined with anti-PD-1/PD-L1 immunotherapy: Mechanisms, clinical efficacy, and issues.
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ABSTRACT:
SUBMITTER: Zhuang H
PROVIDER: S-EPMC7743005 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
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Abscopal effect of stereotactic radiotherapy combined with anti-PD-1/PD-L1 immunotherapy: Mechanisms, clinical efficacy, and issues.
Cancer communications (London, England) 20201110 12
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Project description:Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1), and programmed cell death ligand-1 (PD-L1) have been approved for a variety of malignant tumors and are widely used to treat patients with metastatic disease. However, the efficacy of PD-1 inhibitors is limited due to tumor heterogeneity, high tumor burden, and "cold" tumor microenvironment. Radiotherapy can improve the anti-tumor effects of PD-1/PD-L1 inhibitors in various ways. As a new radiotherapy method, stereotactic body radiotherapy (SBRT) or hypofractionated radiotherapy (HFRT) provides higher doses per fraction to the target lesions, thus achieving immune activation effects and overcoming tumor resistance to anti-PD-1/PD-L1 treatment, which significantly improves the local and distant control of tumors. However, for different metastatic situations, radiotherapy plays different roles in the combination therapy. In oligometastatic status, radiotherapy can be used as a local radical treatment aiming to eliminate cancers in cooperation with systemic PD-1 inhibitors. In other circumstances, like bulky metastasis or multiple metastatic tumors, radiotherapy can be used as adjuvant to systemic immunotherapy. This review focuses on the underlying mechanisms and optimization strategies for the combination of radiotherapy and anti-PD-1/PD-L1 therapy in metastatic disease.
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Project description:PurposeIn this study, we aimed to assess the abscopal effect (AE) after CyberKnife stereotactic body radiotherapy (SBRT) in metastatic breast cancer patients without immunotherapy.MethodsWe reviewed breast cancer patients who received SBRT with a fraction size of ≥ 6 Gy for metastatic lesions between July 2008 and December 2021. We selected patients who had at least one measurable extracranial lesion in addition to SBRT target lesions and were not treated with immunotherapy. A total of 40 SBRT cases from 34 patients were included in the analysis. The AE was defined as occurring before the overall progression of the disease, regardless of the use of systemic treatment.ResultsThe median follow-up duration was 16.4 months. Among 40 SBRT cases, the AE was observed in 10 (25.0%) with a median interval of 2.1 months. Of these lesions, 70.0% did not progress for one year. In multivariate logistic regression analysis, no change in systemic treatment after SBRT was significantly associated with an increase in the AE (odds ratio [OR] = 1.428, 95% confidence interval [CI] = 1.108 - 1.841, p = 0.009). A post-SBRT neutrophil-to-lymphocyte ratio (NLR) of < 2 marginally increased the AE (OR = 1.275, 95% CI = 0.998 - 1.629, p = 0.060). However, a high SBRT dose and large planning target volume did not (p = 0.858 and 0.152, respectively) in univariate analysis.ConclusionsOne out of four patients experienced the AE after SBRT in the absence of immunotherapy. The AE could occur more frequently when systemic treatment remains unchanged, and patients have a low NLR after SBRT.
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Project description:Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression.
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Project description:At present, whole-brain radiation therapy/stereotactic radiosurgery is one of the main local treatments for brain metastasis of non-small-cell lung cancer (NSCLC). Currently, it has been proved that radiotherapy (RT) can regulate the immune response, and small-sample studies have shown that patients with NSCLC brain metastases (BMs) can benefit from RT combined with immunotherapy (IO). However, the efficacy and safety of the combination treatment have not been deeply elaborated. Notably, as a challenge that is still being explored, the timing of RT combined with IO is likely to be an important factor affecting efficacy and prognosis. This article reviews the current application and challenges of RT combined with IO from the perspectives of molecular mechanism, combination timing, safety, and efficacy. The purpose is to provide information on clinical evidence-based medicine of combination between RT with IO. For further investigation, we also discuss the major challenges and prospects of RT combined with IO in NSCLC BMs.
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Project description:We investigated the influence of PD-1 expression on the systemic antitumor response (abscopal effect) induced by stereotactic ablative radiotherapy (SABR) in preclinical melanoma and renal cell carcinoma models. We compared the SABR-induced antitumor response in PD-1-expressing wild-type (WT) and PD-1-deficient knockout (KO) mice and found that PD-1 expression compromises the survival of tumor-bearing mice treated with SABR. None of the PD-1 WT mice survived beyond 25 days, whereas 20% of the PD-1 KO mice survived beyond 40 days. Similarly, PD-1-blocking antibody in WT mice was able to recapitulate SABR-induced antitumor responses observed in PD-1 KO mice and led to increased survival. The combination of SABR plus PD-1 blockade induced near complete regression of the irradiated primary tumor (synergistic effect), as opposed to SABR alone or SABR plus control antibody. The combination of SABR plus PD-1 blockade therapy elicited a 66% reduction in size of nonirradiated, secondary tumors outside the SABR radiation field (abscopal effect). The observed abscopal effect was tumor specific and was not dependent on tumor histology or host genetic background. The CD11a(high) CD8(+) T-cell phenotype identifies a tumor-reactive population, which was associated in frequency and function with a SABR-induced antitumor immune response in PD-1 KO mice. We conclude that SABR induces an abscopal tumor-specific immune response in both the irradiated and nonirradiated tumors, which is potentiated by PD-1 blockade. The combination of SABR and PD-1 blockade has the potential to translate into a potent immunotherapy strategy in the management of patients with metastatic cancer.
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Project description:Immune checkpoint inhibitor (ICI) resistance in advanced hepatocellular carcinoma (HCC)poses a major therapeutic challenge. Here, we report a phase 2 trial evaluating stereotactic bodyradiotherapy (SBRT) combined with the anti-PD-1 antibody sintilimab and bevacizumabbiosimilar (lBI305) to re-sensitize ICI-refractory HCC. Twenty-one patients with progressiveHCC after prior ICI therapy received SBRT (25-50 Gy in 5 fractions) followed by sintilimab(200 mg) and IBl305 (15 mgkg) every 3 weeks. The primary endpoint, objective response rate(ORR) in non-irradiated lesions, was 33.3% (7/21), with a disease control rate of66.7%(14/21)Median progression-free survival (PFS) was 6.2 months (95% CI 3.7-15.1), and estimatedmedian overall survival (OS) was 24.4 months (95% CI 9.2-NA). SBRT achieved 100% localcontrol, while grade >3 treatment-related adverse events occurred in 33.3% of patientsLongitudinal proteomic profiling revealed that responders exhibited lower baseline IFN-y (p0.025) and elevated IL-6 (p=0.002), with post-SBRT increases in IFN-y, IL-2, and IL-6correlating with improved outcomes. These findings demonstrate that SBRT synergizes withdual PD-1/VEGF blockade to overcome ICI resistance, potentially through radiation-inducedimmune remodeling. Biomarker dynamics highlight actionable targets for optimizingcombination therapies in anti-PD-1-refractory HCC.
2025-10-15 | PAD000004 | Pride
Project description:Despite accumulating cases of radiotherapy-induced abscopal effect in the lung cancer with the introduction of immune checkpoint inhibitors (ICIs), the occurrence of this effect remains infrequent and unpredictable to be a therapeutic goal. Here, we showed that the combination of radiotherapy (8Gy*3F) and ICI alleviated the tumor burden at the irradiated site whereas no discernible benefit was observed in the abscopal tumors. RNA-sequencing data showed that extracellular structure organization pathways were enriched in the abscopal tumors after combined therapy, with Sfrp2 being identified as a central hub. SFRP2 expression was observed in cancer-associated fibroblasts (CAFs) and was elevated in abscopal tumors after combined therapy. Blockade of SFRP2 followed by combined radiotherapy and ICI reinvigorated infiltration and cytotoxicity of CD8+ T cells, and elicited regression of abscopal tumors, which was abrogated by CD8α depletion. Mechanistically, in vitro experiments demonstrated that SFRP2+ CAFs induced apoptosis of CD8+ T cells. The spatial transcriptome analysis showed that SFRP2+ CAFs were located in proximity to the vessels and surrounded by abundant macrophages and limited CD8Tex, thereby creating an immunosuppressive perivascular niche, which was validated in paraffin sections of human lung cancer. Lineage-tracing assays showed SFRP2+ CAFs were derived from pericytes. IGF-1 released by irradiated tumors facilitated the transition of pericytes into fibroblasts and stimulated the expression of SFRP2. In summary, SFRP2+ CAFs hijack the abscopal effect from combined radiotherapy and immunotherapy via inducing apoptosis of CD8+ T cells and orchestrating a hostile perivascular niche in the lung cancer. Targeting SFRP2+ CAF may recondition the TME and promote the abscopal effect.
2024-04-01 | GSE261799 | GEO
Project description:BackgroundStereotactic body radiotherapy (SBRT) combined immunotherapy has a synergistic effect on patients with stage IV tumors. However, the efficacy and prognostic factors analysis of SBRT combined immunotherapy for patients with pulmonary oligometastases have rarely been reported in the studies. The purpose of this study is to explore the efficacy and prognostic factors analysis of SBRT combined immunotherapy for patients with oligometastatic lung tumors.MethodsA retrospective analysis was conducted on 43 patients with advanced tumors who received SBRT combined with immunotherapy for pulmonary oligometastases from October 2018 to October 2021. Local control (LC), progression-free survival (PFS), and overall survival (OS) were assessed using the Kaplan-Meier method. Univariate and multivariate analyses of OS were performed using the Cox regression model, and the P value <0.05 was considered statistically significant. The receiver operating characteristic (ROC) curve of neutrophil-to-lymphocyte ratio (NLR) after SBRT was generated. Spearman correlation analysis was used to determine the relationship of planning target volume (PTV) with absolute lymphocyte count (ALC) before and after SBRT and with neutrophil count (NE) after SBRT. Additionally, linear regression was used to examine the relationship between ALC after SBRT and clinical factors.ResultsA total of 43 patients with pulmonary oligometastases receiving SBRT combined with immunotherapy were included in the study. The change in NLR after SBRT was statistically significant (P<0.001). At 1 and 2 years, respectively, the LC rates were 90.3% and 87.5%, the OS rates were 83.46% and 60.99%, and the PFS rates were 69.92% and 54.25%, with a median PFS of 27.00 (17.84-36.13) months. Univariate and multivariate Cox regression analyses showed that a shorter interval between radiotherapy and immunization [≤21 days; hazard ratio (HR) =1.10, 95% confidence interval (CI): 0.06-0.89; P=0.02] and a low NLR after SBRT (HR =0.24, 95% CI: 1.01-1.9; P=0.03) were associated with improved OS. The ROC curve identified 4.12 as the cutoff value for predicting OS based on NLR after SBRT. NLR after SBRT ≤4.12 significantly extended OS compared to NLR after SBRT >4.12 (log-rank P=0.001). Spearman correlation analysis and linear regression analysis showed that PTV was negatively correlated with ALC after SBRT.ConclusionsOur preliminary research shows that SBRT combined with immunotherapy has a good effect, and NLR after SBRT is a poor prognostic factor for OS. Larger PTV volume is associated with decreased ALC after SBRT.
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Project description:BackgroundCurrently, due to synergy enhancement of anti-tumor effects and potent stimulation of abscopal effects, combination therapy with irradiation and programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint inhibition (immuno-radiotherapy, iRT) has revolutionized the therapeutic guidelines. It has been demonstrated that tumor-draining lymph nodes (TDLN) are essential for effective antitumor immunity induced by radiotherapy, immunotherapy, or iRT. Given that the function of TDLN in iRT remains unclear, this study aimed to investigate the function and mechanism of TDLN in iRT-induced abscopal effects.MethodsThe function of TDLN was evaluated using unilateral or bilateral MC38 and B16F10 subcutaneous tumor models with or without indicated TDLN. The flow cytometry, multiple immunofluorescence analysis, and NanoString analysis were utilized to detect the composition and function of the immune cells in the primary and abscopal tumor microenvironment. Additionally, we tempted to interrogate the possible mechanisms via RNA-sequencing of tumor-infiltrating lymphocytes and TDLN.ResultsTDLN deficiency impaired the control of tumor growth by monotherapy. Bilateral TDLN removal rather than unilateral TDLN removal substantially curtailed iRT-stimulated anti-tumor and abscopal effects. Furthermore, in the absence of TDLN, the infiltration of CD45+ and CD8+ T cells was substantially reduced in both primary and abscopal tumors, and the anti-tumor function of CD8+ T cells was attenuated as well. Additionally, the polarization of tumor-associated macrophages in primary and abscopal tumors were found to be dependent on intact bilateral TDLN. RNA-sequencing data indicated that impaired infiltration and anti-tumor effects of immune cells partially attributed to the altered secretion of components from the tumor microenvironment.ConclusionsTDLN play a critical role in iRT by promoting the infiltration of CD8+ T cells and maintaining the M1/M2 macrophage ratio.
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Project description:Radiotherapy can boost the therapeutic response to immune checkpoint inhibitors (ICIs) by recruiting T lymphocytes and upregulating PD-L1 expression within the tumor microenvironment (TME). However, in some cases, tumor PD-L1 expression cannot be induced, even in the presence of abundant T lymphocytes, in locally advanced colorectal cancer patients who receive preoperative neoadjuvant concurrent chemoradiotherapy (CCRT). In this study, we found that PD-L1 promoter methylation is negatively correlated with tumor PD-L1 expression and is an independent biomarker for locally advanced colorectal cancer patients. PD-L1 methylation (mCD274) was significantly associated with shorter disease-free survival (cg15837913 loci, p = .0124). By multivariate Cox proportional hazards analyses including influent factors, mCD274 was classified as an independent prognostic factor for poor 5-year DFS [cg15837913, hazard ratio: HR = 4.06, 95% CI = 1.407-11.716, p = .01]. We found that the immunomodulatory agent DNA methyltransferase inhibitor (DNMTi) led to demethylation of the PD-L1 promoter and increased radiotherapy-induced PD-L1 upregulation via interferon β (IFNβ). DNMTi not only induced tumor PD-L1 expression but increased the expression of immune-related genes as well as intratumoral T cell infiltration in vivo. Furthermore, DNMTi strongly enhanced the response to combined treatment with radiotherapy and anti-PD-L1 inhibitors, and prolonged survival in microsatellite stability (MSS) colorectal model. Therefore, DNMTi remodeled the tumor microenvironment to improve the effect of radiotherapy and anti-PD-L1 immunotherapy by directly triggering tumor PD-L1 expression and eliciting stronger immune responses, which may provide potential clinical benefits to colorectal cancer patients in the future.
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