ABSTRACT
BACKGROUND: Local treatment options for locally recurrent pancreatic adenocarcinoma (LR-PAC) are limited, with median survival time (MST) of 9-13 months (mos) following recurrence. MRI-guided stereotactic body radiation therapy (MRgSBRT) provides the ability to dose escalate while sparing normal tissue. Here we report on the early outcomes of MRgSBRT for LR-PAC. METHODS: Patients with prior resection of pancreatic adenocarcinoma with local recurrence treated with MRgSBRT at a single tertiary referral center from 5-2021 to 2-2023 were identified from our prospective database. MRgSBRT was delivered to 40-50 Gy in 4-5 fractions with target and OAR delineation per institutional standards. Endpoints included local control per RECIST v1.1, distant failure, overall survival (OS), and acute and chronic toxicities per Common Terminology Criteria for Adverse Events, v5. RESULTS: Fifteen patients with LR-PAC were identified with median follow-up of 10.6 mos (2.8-26.5 mos) from MRgSBRT. There were 8 females and 7 males, with a median age of 69 years (50-83). One patient underwent neoadjuvant radiation for 50.4 Gy in 28 fractions followed by resection, and one underwent adjuvant radiation for 45 Gy in 25 fractions prior to recurrence. MRgSBRT was delivered a median of 18.8 mos (3.5-52.8 mos) following resection. OS following recurrence at 6 and 12 mos were 87% and 51%, respectively, with a median survival time of 14.1 mos (3.2-27.4 mos). Three patients experienced local failure at 5.9, 7.8, and 16.6 months from MgSBRT with local control of 92.3% and 83.9% at 6 and 12 months. 10 patients experienced distant failure at a median of 2.9 mos (0.3-6.7 mos). Grade 1-2 acute GI toxicity was noted in 47% of patients, and chronic GI toxicity in 31% of patients. No grade > 3 toxicities were noted. CONCLUSIONS: This is the first report on toxicity and outcomes of MRgSBRT for LR-PAC in the literature. MRgSBRT is a safe, feasible treatment modality with the potential for improved local control in this vulnerable population. Future research is necessary to better identify which patients yield the most benefit from MRgSBRT, which should continue to be used with systemic therapy as tolerated. TRIAL REGISTRATION: Jefferson IRB#20976, approved 2/17/21.
Subject(s)
Adenocarcinoma , Neoplasm Recurrence, Local , Pancreatic Neoplasms , Radiosurgery , Humans , Male , Pancreatic Neoplasms/radiotherapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/surgery , Female , Aged , Radiosurgery/methods , Radiosurgery/adverse effects , Middle Aged , Adenocarcinoma/radiotherapy , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Adenocarcinoma/mortality , Neoplasm Recurrence, Local/radiotherapy , Neoplasm Recurrence, Local/pathology , Aged, 80 and over , Magnetic Resonance Imaging , Radiotherapy, Image-Guided/methods , Survival Rate , Prospective Studies , Retrospective StudiesABSTRACT
BACKGROUND AND PURPOSE: Radiation dose escalation may improve local control (LC) and overall survival (OS) in select pancreatic ductal adenocarcinoma (PDAC) patients. We prospectively evaluated the safety and efficacy of ablative stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for borderline resectable (BRPC) and locally advanced pancreas cancer (LAPC). The primary endpoint of acute grade ≥ 3 gastrointestinal (GI) toxicity definitely related to SMART was previously published with median follow-up (FU) 8.8 months from SMART. We now present more mature outcomes including OS and late toxicity. MATERIALS AND METHODS: This prospective, multi-center, single-arm open-label phase 2 trial (NCT03621644) enrolled 136 patients (LAPC 56.6 %; BRPC 43.4 %) after ≥ 3 months of any chemotherapy without distant progression and CA19-9 ≤ 500 U/mL. SMART was delivered on a 0.35 T MR-guided system prescribed to 50 Gy in 5 fractions (biologically effective dose10 [BED10] = 100 Gy). Elective coverage was optional. Surgery and chemotherapy were permitted after SMART. RESULTS: Mean age was 65.7 years (range, 36-85), induction FOLFIRINOX was common (81.7 %), most received elective coverage (57.4 %), and 34.6 % had surgery after SMART. Median FU was 22.9 months from diagnosis and 14.2 months from SMART, respectively. 2-year OS from diagnosis and SMART were 53.6 % and 40.5 %, respectively. Late grade ≥ 3 toxicity definitely, probably, or possibly attributed to SMART were observed in 0 %, 4.6 %, and 11.5 % patients, respectively. CONCLUSIONS: Long-term outcomes from the phase 2 SMART trial demonstrate encouraging OS and limited severe toxicity. Additional prospective evaluation of this novel strategy is warranted.
Subject(s)
Pancreatic Neoplasms , Radiosurgery , Humans , Aged , Pancreatic Neoplasms/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Radiotherapy Planning, Computer-Assisted , Radiosurgery/adverse effectsABSTRACT
PURPOSE: Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted a prospective study evaluating the safety of 5-fraction Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC). METHODS AND MATERIALS: Patients with LAPC or BRPC were eligible for this multi-institutional, single-arm, phase 2 trial after ≥3 months of systemic therapy without evidence of distant progression. Fifty gray in 5 fractions was prescribed on a 0.35T MR-guided radiation delivery system. The primary endpoint was acute grade ≥3 gastrointestinal (GI) toxicity definitely attributed to SMART. RESULTS: One hundred thirty-six patients (LAPC 56.6%, BRPC 43.4%) were enrolled between January 2019 and January 2022. Mean age was 65.7 (36-85) years. Head of pancreas lesions were most common (66.9%). Induction chemotherapy mostly consisted of (modified)FOLFIRINOX (65.4%) or gemcitabine/nab-paclitaxel (16.9%). Mean CA19-9 after induction chemotherapy and before SMART was 71.7 U/mL (0-468). On-table adaptive replanning was performed for 93.1% of all delivered fractions. Median follow-up from diagnosis and SMART was 16.4 and 8.8 months, respectively. The incidence of acute grade ≥3 GI toxicity possibly or probably attributed to SMART was 8.8%, including 2 postoperative deaths that were possibly related to SMART in patients who had surgery. There was no acute grade ≥3 GI toxicity definitely related to SMART. One-year overall survival from SMART was 65.0%. CONCLUSIONS: The primary endpoint of this study was met with no acute grade ≥3 GI toxicity definitely attributed to ablative 5-fraction SMART. Although it is unclear whether SMART contributed to postoperative toxicity, we recommend caution when pursuing surgery, especially with vascular resection after SMART. Additional follow-up is ongoing to evaluate late toxicity, quality of life, and long-term efficacy.
Subject(s)
Pancreatic Neoplasms , Radiosurgery , Humans , Aged , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/radiotherapy , Pancreatic Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prospective Studies , Radiotherapy Planning, Computer-Assisted , Quality of Life , Pancreas , Magnetic Resonance Spectroscopy , Radiosurgery/methods , Pancreatic NeoplasmsABSTRACT
Pancreatic cancer is one of the most lethal cancers, due to its uniquely aggressive behavior and resistance to therapy. The tumor microenvironment of pancreatic cancer is immunosuppressive, and attempts at utilizing immunotherapies have been unsuccessful. Radiation therapy (RT) results in immune activation and antigen presentation in other cancers, but in pancreatic cancer has had limited success in stimulating immune responses. RT activates common pathways of fibrosis and chronic inflammation seen in pancreatic cancer, resulting in immune suppression. Here we describe the pancreatic tumor microenvironment with regard to fibrosis, myeloid and lymphoid cells, and the impact of RT. We also describe strategies of targeting these pathways that have promise to improve outcomes by harnessing the cytotoxic and immune-activating aspects of RT.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Tumor Microenvironment , Pancreatic Neoplasms/radiotherapy , Immunotherapy , Fibrosis , Carcinoma, Pancreatic Ductal/therapy , Pancreatic NeoplasmsABSTRACT
INTRODUCTION: Radiation therapy (XRT) has been investigated as a possible treatment for high-risk non-muscle invasive bladder cancer (NMIBC) with the goal of bladder preservation, especially with the ongoing Bacillus Calmette-Guerin (BCG) shortage. Yet, little is known about the clinical efficacy and the quality of evidence supporting XRT for NMIBC. Herein, we performed a systematic review and meta-analysis to evaluate XRT in the treatment of patients with high-risk NMIBC. METHODS: Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and Web of Science were searched for high-risk NMIBC (high grade T1, T1/Ta with associated risk features: carcinoma in-situ (CIS), multifocality, > 5cm in diameter, and/or multiple recurrences) treated with primary XRT. Outcomes evaluated were recurrence-free survival (RFS), cancer-specific-survival (CSS), overall survival (OS), and salvage cystectomy and progression to metastatic disease rates. A meta-analysis was performed to assess outcomes for XRT in NMIBC. RESULTS: Overall,13 studies including 746 patients met the search criteria. The 5-year rates of RFS, CSS and OS were 54% (95% CIâ¯=â¯38% - 70%), 86% (95% CIâ¯=â¯80% - 92%), and 72% (95% CIâ¯=â¯64% - 79%). Notably, 13% of patients proceeded to salvage radical cystectomy and 9% developed metastatic disease. All studies were of poor quality, comprising single institution and retrospective studies with only one clinical trial. CONCLUSION: XRT for high-risk NMIBC provides some degree of oncologic control, although distant progression was noted. In the setting of the low-quality evidence, a prospective clinical trial is needed to clearly define the risks and benefits of this approach.
Subject(s)
Urinary Bladder Neoplasms/radiotherapy , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle AgedABSTRACT
BACKGROUND: Numerous trials combining radiation therapy (RT) and immunotherapy in head and neck squamous cell carcinoma (HNSCC) are failing. Using preclinical immune cold models of HNSCC resistant to RT-immune checkpoint inhibitors, we investigate therapeutic approaches of overcoming such resistance by examining the differential microenvironmental response to RT. METHODS: We subjected two HPV-negative orthotopic mouse models of HNSCC to combination RT, regulatory T cells (Treg) depletion, and/or CD137 agonism. Tumor growth was measured and intratumorous and lymph node immune populations were compared among treatment groups. Human gene sets, genetically engineered mouse models DEREG and BATF3-/-, flow and time-of-flight cytometry, RNA-Seq, Treg adoptive transfer studies, and in vitro experiments were used to further evaluate the role of dendritic cells (DCs) and Tregs in these treatments. RESULTS: In MOC2 orthotopic tumors, we find no therapeutic benefit to targeting classically defined immunosuppressive myeloids, which increase with RT. In these radioresistant tumors, supplementing combination RT and Treg depletion with anti-CD137 agonism stimulates CD103+ DC activation in tumor-draining lymph nodes as characterized by increases in CD80+ and CCR7+ DCs, resulting in a CD8 T cell-dependent response. Simultaneously, Tregs are reprogrammed to an effector phenotype demonstrated by increases in interferonγ+, tumor necrosis factorα+, PI3K+, pAKT+ and Eomes+ populations as well as decreases in CTLA4+ and NRP-1+ populations. Tumor eradication is observed when RT is increased to an 8 Gy x 5 hypofractionated regimen and combined with anti-CD25+ anti-CD137 treatment. In a human gene set from oral squamous cell carcinoma tumors, high Treg number is associated with earlier recurrence. CONCLUSIONS: Regulating Treg functionality and DC activation status within the lymph node is critical for generating a T cell effector response in these highly radioresistant tumors. These findings underscore the plasticity of Tregs and represent a new therapeutic opportunity for reprogramming the tumor microenvironment in HNSCCs resistant to conventional radioimmunotherapy approaches.
Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Dendritic Cells/drug effects , Drug Resistance, Neoplasm , Head and Neck Neoplasms/therapy , Immune Checkpoint Inhibitors/pharmacology , Immunotherapy , Radiation Dose Hypofractionation , Radiation Tolerance , Squamous Cell Carcinoma of Head and Neck/therapy , T-Lymphocytes, Regulatory/drug effects , Animals , Basic-Leucine Zipper Transcription Factors/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , Cell Line, Tumor , Combined Modality Therapy , Dendritic Cells/immunology , Dendritic Cells/metabolism , Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/pathology , Interleukin-2 Receptor alpha Subunit/antagonists & inhibitors , Interleukin-2 Receptor alpha Subunit/metabolism , Lymphocyte Depletion , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Repressor Proteins/genetics , Repressor Proteins/metabolism , Squamous Cell Carcinoma of Head and Neck/immunology , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/pathology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Tumor Burden , Tumor Microenvironment , Tumor Necrosis Factor Receptor Superfamily, Member 9/antagonists & inhibitors , Tumor Necrosis Factor Receptor Superfamily, Member 9/metabolismABSTRACT
Stromal fibrosis activates prosurvival and proepithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell-surface proteins, a disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after radiation therapy (RT). RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with ephrinB2 FC protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after RT and identifies a targetable pathway to enhance RT efficacy. SIGNIFICANCE: Targeting a previously unidentified adaptive resistance mechanism to radiation therapy in PDAC tumors in combination with radiation therapy could increase survival of the 40% of PDAC patients with locally advanced disease.See related commentary by Garcia Garcia et al., p. 3158 GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3255/F1.large.jpg.
Subject(s)
ADAM10 Protein/metabolism , Amyloid Precursor Protein Secretases/metabolism , Carcinoma, Pancreatic Ductal/radiotherapy , Epithelial-Mesenchymal Transition , Fibrosis/pathology , Gamma Rays/adverse effects , Membrane Proteins/metabolism , Pancreatic Neoplasms/radiotherapy , Radiation Injuries/pathology , ADAM10 Protein/antagonists & inhibitors , ADAM10 Protein/genetics , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/genetics , Animals , Antifibrotic Agents/therapeutic use , Apoptosis , Carcinoma, Pancreatic Ductal/pathology , Cell Movement , Cell Proliferation , Ephrin-B2/blood , Female , Fibrosis/drug therapy , Fibrosis/etiology , Fibrosis/metabolism , Humans , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Pancreatic Neoplasms/pathology , Prognosis , Radiation Injuries/drug therapy , Radiation Injuries/etiology , Radiation Injuries/metabolism , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) has a heterogeneous tumor microenvironment (TME) comprised of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, neutrophils, regulatory T cells, and myofibroblasts. The precise mechanisms that regulate the composition of the TME and how they contribute to radiotherapy (RT) response remain poorly understood. In this study, we analyze changes in immune cell populations and circulating chemokines in patient samples and animal models of pancreatic cancer to characterize the immune response to radiotherapy. Further, we identify STAT3 as a key mediator of immunosuppression post-RT. We found granulocytic MDSCs (G-MDSCs) and neutrophils to be increased in response to RT in murine and human PDAC samples. We also found that RT-induced STAT3 phosphorylation correlated with increased MDSC infiltration and proliferation. Targeting STAT3 using an anti-sense oligonucleotide in combination with RT circumvented RT-induced MDSC infiltration, enhanced the proportion of effector T cells, and improved response to RT. In addition, STAT3 inhibition contributed to the remodeling of the PDAC extracellular matrix when combined with RT, resulting in decreased collagen deposition and fibrotic tissue formation. Collectively, our data provide evidence that targeting STAT3 in combination with RT can mitigate the pro-tumorigenic effects of RT and improve tumor response.
Subject(s)
Carcinoma, Pancreatic Ductal/radiotherapy , Gamma Rays , Myeloid-Derived Suppressor Cells/immunology , Oligonucleotides, Antisense/genetics , Pancreatic Neoplasms/radiotherapy , STAT3 Transcription Factor/antagonists & inhibitors , Animals , Apoptosis , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/pathology , Cell Proliferation , Female , Humans , Immunosuppression Therapy , Mice , Mice, Inbred C57BL , Mice, Nude , Myeloid-Derived Suppressor Cells/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Prognosis , STAT3 Transcription Factor/genetics , T-Lymphocytes, Regulatory/immunology , Tumor Cells, Cultured , Tumor MicroenvironmentABSTRACT
BACKGROUND: The role of neoadjuvant stereotactic body radiation therapy (SBRT) in patients with borderline resectable pancreas cancer (BRPC) and locally advanced pancreas cancer (LAPC) remains controversial. METHODS: We retrospectively evaluated BRPC and LAPC patients treated at our institution who underwent 2-3 months of chemotherapy followed by SBRT to a dose of 30-33 Gy. Overall survival (OS) and recurrence-free survival (RFS) were estimated and compared by Kaplan-Meier and log-rank methods. RESULTS: We identified 103 (85 BRPC and 18 LAPC) patients treated per our neoadjuvant paradigm between 2011 and 2018, with resectability based on NCCN definitions. Median follow up was 25 months. Of patients completing neoadjuvant therapy, 73 (71%) underwent definitive resection. Seventy-one (97%) patients with definitively resected tumors had R0 resection and 5 (7%) had a complete pathologic response CR to neoadjuvant therapy. The median overall survival (OS) of the cohort was 24 months. Those with a complete or marked pathologic response had significantly better OS than those with a moderate response (41 vs 24 months, p < 0.02) and patients unable to undergo definitive surgery (17 months, p < 0.0003). Six resected patients experienced grade ≥3 surgical complications. CONCLUSIONS: Neoadjuvant chemotherapy and SBRT are associated with promising pathologic response rates and R0 resection rates, with acceptable perioperative morbidity.
Subject(s)
Pancreatic Neoplasms , Radiosurgery , Antineoplastic Combined Chemotherapy Protocols , Dose Fractionation, Radiation , Humans , Neoadjuvant Therapy/adverse effects , Pancreatic Neoplasms/surgery , Radiosurgery/adverse effects , Retrospective StudiesABSTRACT
BACKGROUND: Persistent controversy exists with regard to how and when patients with head and neck cancer should undergo imaging after definitive therapy. The current study was conducted to evaluate whether the type of imaging modality used in posttreatment imaging impacts cancer-specific survival for patients with advanced head and neck squamous cell carcinoma. METHODS: A retrospective study of National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program-Medicare-linked data in patients with an advanced stage of the 3 most common head and neck malignancies (oral cavity, oropharynx, and larynx) was conducted. Hazard ratios and 95% CIs for cancer-specific survival were estimated for patients diagnosed with any of these cancers between 2006 and 2015. RESULTS: Significant improvement with regard to cancer-specific survival was observed among patients with American Joint Committee on Cancer stage III and stage IVA laryngeal cancer who underwent positron emission tomography (PET) and/or computed tomography (CT) imaging during the first 6 months after receipt of definitive treatment (hazard ratio, 0.517; 95% CI, 0.33-0.811) compared with those who underwent CT. There was a trend toward an improvement in cancer-specific survival among patients with oral cavity or oropharyngeal malignancies who underwent PET/CT imaging, but it did not reach statistical significance. CONCLUSIONS: Compared with CT imaging, posttreatment imaging with PET was associated with improved survival in patients with advanced laryngeal carcinoma.
Subject(s)
Larynx/diagnostic imaging , Mouth/diagnostic imaging , Oropharynx/diagnostic imaging , Squamous Cell Carcinoma of Head and Neck/diagnostic imaging , Aged , Disease-Free Survival , Fluorodeoxyglucose F18 , Humans , Laryngeal Neoplasms , Larynx/pathology , Male , Medicare/economics , Middle Aged , Mouth/pathology , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/diagnostic imaging , Neoplasm Recurrence, Local/pathology , Oropharynx/pathology , Positron-Emission Tomography , Squamous Cell Carcinoma of Head and Neck/diagnosis , Squamous Cell Carcinoma of Head and Neck/epidemiology , Squamous Cell Carcinoma of Head and Neck/pathology , United StatesABSTRACT
The aggressive nature of glioblastoma multiforme (GBM) may be attributed to the dysregulation of pathways driving both proliferation and invasion. EphrinB2, a membrane-bound ligand for some of the Eph receptors, has emerged as a critical target regulating these pathways. In this study, we investigated the role of ephrinB2 in regulating proliferation and invasion in GBM using intracranial and subcutaneous xenograft models. The Cancer Genome Atlas analysis suggested high transcript and low methylation levels of ephrinB2 as poor prognostic indicators in GBM, consistent with its role as an oncogene. EphrinB2 knockdown, however, increased tumor growth, an effect that was reversed by ephrinB2 Fc protein. This was associated with EphB4 receptor activation, consistent with the data showing a significant decrease in tumor growth with ephrinB2 overexpression. Mechanistic analyses showed that ephrinB2 knockdown has anti-invasive but pro-proliferative effects in GBM. EphB4 stimulation following ephrinB2 Fc treatment in ephrinB2 knockdown tumors was shown to impart strong anti-proliferative and anti-invasive effects, which correlated with decrease in PCNA, p-ERK, vimentin, Snail, Fak, and increase in the E-cadherin levels. Overall, our study suggests that ephrinB2 cannot be used as a sole therapeutic target. Concomitant inhibition of ephrinB2 signaling with EphB4 activation is required to achieve maximal therapeutic benefit in GBM.
Subject(s)
Biomarkers, Tumor/metabolism , Cell Proliferation , Ephrin-B2/metabolism , Gene Expression Regulation, Neoplastic , Glioblastoma/pathology , Receptor, EphB4/metabolism , Animals , Apoptosis , Biomarkers, Tumor/genetics , Cell Movement , Ephrin-B2/genetics , Female , Glioblastoma/genetics , Glioblastoma/metabolism , Humans , Mice , Mice, Nude , Neoplasm Invasiveness , Phosphorylation , Prognosis , Receptor, EphB4/genetics , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Fibroblasts are a key component of the tumor microenvironment (TME) that can serve as a scaffold for tumor cell migration and augment the tumor's ability to withstand harsh conditions. When activated by external or endogenous stimuli, normal fibroblasts become cancer associated fibroblasts (CAFs), a heterogeneous group of stromal cells in the tumor that are phenotypically and epigenetically different from normal fibroblasts. Dynamic crosstalk between cancer cells, immune cells, and CAFs through chemokines and surface signaling makes the TME conducive to tumor growth. When activated, CAFs promote tumorigenesis and metastasis through several phenomena including regulation of tumor immunity, metabolic reprogramming of the TME, extracellular matrix remodeling and contraction, and induction of therapeutic resistance. Ionizing radiation (radiation theraphy [RT]) is a potent immunological stimulant that has been shown to increase cytotoxic Teff infiltration and IFN-I stimulated genes. RT, however, is unable to overcome the infiltration and activation of immunosuppressive cells which can contribute to tumor progression. Another paradox of RT is that, while very effective at killing cancer cells, it can contribute to the formation of CAFs. This review examines how the interplay between CAFs and immune cells during RT contributes to organ fibrosis, immunosuppression, and tumor growth. We focus on targeting mechanistic pathways of CAF formation as a potentially effective strategy not only for preventing organ fibrosis, but also in hampering tumor progression in response to RT.
Subject(s)
Cancer-Associated Fibroblasts/immunology , Cancer-Associated Fibroblasts/pathology , Neoplasms/immunology , Neoplasms/pathology , Animals , Cancer-Associated Fibroblasts/radiation effects , Fibrosis/immunology , Fibrosis/pathology , Humans , Neoplasms/radiotherapy , Radiotherapy/methods , Tumor Microenvironment/immunology , Tumor Microenvironment/radiation effectsABSTRACT
BACKGROUND: The optimal imaging for the staging of oropharyngeal cancer is not well defined. METHODS: The linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database for 2006 through 2011 was used to compare patient characteristics and hospital region by the initial imaging modality used for patients with oropharyngeal cancer. The primary outcome was 3-year cancer-specific survival (CSS). Cox proportional hazards models were adjusted for imaging, age, sex, region, education, race, American Joint Committee on Cancer stage of disease, and treatment, which were examined using backward elimination. The authors also explored how initial imaging use varied by patient characteristics and hospital region. RESULTS: A total of 1765 patients underwent initial diagnostic imaging. Of those, approximately 11.4% (202 patients) received computed tomography (CT) alone as their initial imaging modality, 5.2% (91 patients) underwent magnetic resonance imaging (MRI) without positron emission tomography (PET), and 83.3% (1472 patients) had initial imaging that included PET. The overall 3-year CSS rate for the entire population was 63.7%. In the adjusted survival models compared by initial imaging modality, patients who underwent a PET examination were found to have higher survival than those who underwent CT alone or MRI, respectively (hazard ratio, 1.337 [95% CI, 1.001-1.785; P = .0491]; and hazard ratio, 1.748 [95% CI, 1.2-2.545; P = .0036]). CONCLUSIONS: Among patients with oropharyngeal cancer, initial staging with PET imaging was associated with improved 3-year CSS compared with initial staging with MRI or CT.
Subject(s)
Oropharyngeal Neoplasms/diagnostic imaging , Oropharyngeal Neoplasms/mortality , Positron-Emission Tomography , Aged , Female , Humans , Magnetic Resonance Imaging/statistics & numerical data , Male , Positron-Emission Tomography/statistics & numerical data , SEER Program , Tomography, X-Ray Computed/statistics & numerical dataABSTRACT
PURPOSE: A driving factor in pancreatic ductal adenocarcinoma (PDAC) treatment resistance is the tumor microenvironment, which is highly immunosuppressive. One potent immunologic adjuvant is radiotherapy. Radiation, however, has also been shown to induce immunosuppressive factors, which can contribute to tumor progression and formation of fibrotic tumor stroma. To capitalize on the immunogenic effects of radiation and obtain a durable tumor response, radiation must be rationally combined with targeted therapies to mitigate the influx of immunosuppressive cells and fibrosis. One such target is ephrinB2, which is overexpressed in PDAC and correlates negatively with prognosis.Experimental Design: On the basis of previous studies of ephrinB2 ligand-EphB4 receptor signaling, we hypothesized that inhibition of ephrinB2-EphB4 combined with radiation can regulate the microenvironment response postradiation, leading to increased tumor control in PDAC. This hypothesis was explored using both cell lines and in vivo human and mouse tumor models. RESULTS: Our data show this treatment regimen significantly reduces regulatory T-cell, macrophage, and neutrophil infiltration and stromal fibrosis, enhances effector T-cell activation, and decreases tumor growth. Furthermore, our data show that depletion of regulatory T cells in combination with radiation reduces tumor growth and fibrosis. CONCLUSIONS: These are the first findings to suggest that in PDAC, ephrinB2-EphB4 interaction has a profibrotic, protumorigenic role, presenting a novel and promising therapeutic target.
Subject(s)
Ephrin-B2/metabolism , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Receptor, EphB4/metabolism , Tumor Microenvironment/drug effects , Tumor Microenvironment/radiation effects , Animals , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Agents, Immunological/therapeutic use , Biomarkers , Cell Line, Tumor , Disease Models, Animal , Ephrin-B2/antagonists & inhibitors , Ephrin-B2/genetics , Female , Flow Cytometry , Gene Expression , Gene Knockdown Techniques , Humans , Immunohistochemistry , Mice , Molecular Targeted Therapy/adverse effects , Molecular Targeted Therapy/methods , Neutrophils/immunology , Neutrophils/metabolism , Pancreatic Neoplasms/therapy , Radiotherapy/adverse effects , Radiotherapy/methods , Receptor, EphB4/antagonists & inhibitors , Receptor, EphB4/genetics , Signal Transduction/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Identifying targets present in the tumor microenvironment that contribute to immune evasion has become an important area of research. In this study, we identified EphB4-ephrin-B2 signaling as a regulator of both innate and adaptive components of the immune system. EphB4 belongs to receptor tyrosine kinase family that interacts with ephrin-B2 ligand at sites of cell-cell contact, resulting in bidirectional signaling. We found that EphB4-ephrin-B2 inhibition alone or in combination with radiation (RT) reduced intratumoral regulatory T cells (Tregs) and increased activation of both CD8+ and CD4+Foxp3- T cells compared with the control group in an orthotopic head and neck squamous cell carcinoma (HNSCC) model. We also compared the effect of EphB4-ephrin-B2 inhibition combined with RT with combined anti-PDL1 and RT and observed similar tumor growth suppression, particularly at early time-points. A patient-derived xenograft model showed reduction of tumor-associated M2 macrophages and favored polarization towards an antitumoral M1 phenotype following EphB4-ephrin-B2 inhibition with RT. In vitro, EphB4 signaling inhibition decreased Ki67-expressing Tregs and Treg activation compared with the control group. Overall, our study is the first to implicate the role of EphB4-ephrin-B2 in tumor immune response. Moreover, our findings suggest that EphB4-ephrin-B2 inhibition combined with RT represents a potential alternative for patients with HNSCC and could be particularly beneficial for patients who are ineligible to receive or cannot tolerate anti-PDL1 therapy. SIGNIFICANCE: These findings present EphB4-ephrin-B2 inhibition as an alternative to anti-PDL1 therapeutics that can be used in combination with radiation to induce an effective antitumor immune response in patients with HNSCC.
Subject(s)
Ephrin-B2/metabolism , Head and Neck Neoplasms/metabolism , Receptor, EphB4/metabolism , Signal Transduction , Squamous Cell Carcinoma of Head and Neck/metabolism , Tumor Microenvironment/immunology , Chemoradiotherapy , Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/therapy , Heterografts , Humans , Macrophages/immunology , Squamous Cell Carcinoma of Head and Neck/immunology , Squamous Cell Carcinoma of Head and Neck/therapyABSTRACT
OBJECTIVE Recent advancements in molecular biology have identified the BRAF mutation as a common mutation in melanoma. The wide use of BRAF kinase inhibitor ( BRAFi) in patients with metastatic melanoma has been established. The objective of this study was to examine the impact of BRAF mutation status and use of BRAFi in conjunction with stereotactic radiosurgery (SRS). METHODS This was a single-center retrospective study. Patient's charts and electronic records were reviewed for date of diagnosis of primary malignancy, BRAF mutation status, chemotherapies used, date of the diagnosis of CNS metastases, date of SRS, survival, local tumor control after SRS, and adverse events. Patients were divided into 3 groups: Group A, those with mutant BRAF without BRAFi treatment (13 patients); Group B, those with mutant BRAF with BRAFi treatment (17 patients); and Group C, those with wild-type BRAF (35 patients). Within a cohort of 65 patients with the known BRAF mutation status and treated with SRS between 2010 and 2014, 436 individual brain metastases (BMs) were identified. Kaplan-Meier methodology was then used to compare survival based on each binary parameter. RESULTS Median survival times after the diagnosis of melanoma BM and after SRS were favorable in patients with a BRAF mutation and treated with SRS in conjunction with BRAFi (Group B) compared with the patients with wild-type BRAF (Group C, 23 vs 8 months and 13 vs 5 months, respectively; p < 0.01, log-rank test). SRS provided a local tumor control rate of 89.4% in the entire cohort of patients. Furthermore, the local control rate was improved in the patients treated with SRS in conjunction with BRAFi (Group B) compared with patients with wild-type (Group C) or with BRAF mutation but no BRAFi (Group A) as an adjunct treatment for BMs. CONCLUSIONS BRAF mutation status appears to play an important role as a potent prognostic factor in patients harboring melanoma BM. BRAFi in conjunction with SRS may benefit this group of patients in terms of BM survival and SRS with an acceptable safety profile.
Subject(s)
Brain Neoplasms/secondary , Brain Neoplasms/therapy , Melanoma/pathology , Melanoma/therapy , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Radiosurgery , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Brain Neoplasms/enzymology , Brain Neoplasms/genetics , Chemoradiotherapy , Female , Humans , Male , Melanoma/enzymology , Melanoma/genetics , Middle Aged , Prognosis , Proto-Oncogene Proteins B-raf/genetics , Retrospective Studies , Survival Analysis , Young AdultABSTRACT
An in silico screen for myogenic long noncoding RNAs (lncRNAs) revealed nine lncRNAs that are upregulated more than 10-fold in myotubes versus levels in myoblasts. One of these lncRNAs, MyoD upstream noncoding (MUNC, also known as DRR(eRNA)), is encoded 5 kb upstream of the transcription start site of MyoD, a myogenic transcription factor gene. MUNC is specifically expressed in skeletal muscle and exists as in unspliced and spliced isoforms, and its 5' end overlaps with the cis-acting distal regulatory region (DRR) of MyoD. Small interfering RNA (siRNA) of MUNC reduced myoblast differentiation and specifically reduced the association of MyoD to the DRR enhancer and myogenin promoter but not to another MyoD-dependent enhancer. Stable overexpression of MUNC from a heterologous promoter increased endogenous MyoD, Myogenin, and Myh3 (myosin heavy chain, [MHC] gene) mRNAs but not the cognate proteins, suggesting that MUNC can act in trans to promote gene expression but that this activity does not require an induction of MyoD protein. MUNC also stimulates the transcription of other genes that are not recognized as MyoD-inducible genes. Knockdown of MUNC in vivo impaired murine muscle regeneration, implicating MUNC in primary satellite cell differentiation in the animal. We also discovered a human MUNC that is induced during differentiation of myoblasts and whose knockdown decreases differentiation, suggesting an evolutionarily conserved role of MUNC lncRNA in myogenesis. Although MUNC overlaps with the DRR enhancer, our results suggest that MUNC is not a classic cis-acting enhancer RNA (e-RNA) acting exclusively by stimulating the neighboring MyoD gene but more like a promyogenic lncRNA that acts directly or indirectly on multiple promoters to increase myogenic gene expression.
Subject(s)
Cell Differentiation/physiology , Muscle Development/genetics , MyoD Protein/metabolism , Myoblasts/metabolism , RNA, Untranslated/genetics , Animals , Cell Differentiation/genetics , Cell Line , Humans , Mice , Muscle, Skeletal/metabolism , Myogenin/metabolism , RNA, Small Interfering/genetics , Transcriptional Activation/physiologyABSTRACT
A significant portion of the mammalian genome encodes numerous transcripts that are not translated into proteins, termed long non-coding RNAs. Initial studies identifying long non-coding RNAs inferred these RNA sequences were a consequence of transcriptional noise or promiscuous RNA polymerase II activity. However, the last decade has seen a revolution in the understanding of regulation and function of long non-coding RNAs. Now it has become apparent that long non-coding RNAs play critical roles in a wide variety of biological processes. In this review, we describe the current understanding of long non-coding RNA-mediated regulation of cellular processes: differentiation, development, and disease.