Clinicopathologic characteristics and immunotherapy outcomes in SMARCA4-mutant (mut) non-small cell lung cancer (NSCLC).

9577 Background: The catalytic unit of the SWI/SNF chromatin remodeling complex is encoded by the SMARCA4 gene, which is mutated in ~10% of NSCLCs. We sought to characterize the clinicopathologic characteristics and outcomes to immune checkpoint inhibition in SMARCA4-mutant NSCLC. Methods: We collected clinicopathologic and genomic data from patients with NSCLC that had undergone targeted next generation sequencing (NGS) by OncoPanel at the Dana-Farber Cancer Institute. SMARCA4 frameshift, nonsense, and splice-site mutations were considered pathogenic, as were missense mutations if predicted to be pathogenic by Mutation Assessor and Polyphen-2. Clinical outcomes to immune checkpoint inhibition among SMARCA4-mutant NSCLCs were retrospectively assessed. Results: Of 2690 patients with NSCLC, 8% (N = 211) harbored SMARCA4 mutations. Clinicopathological characteristics were balanced between SMARCA4 mut and SMARCA4 wild-type (wt) in terms of age, histology, and PD-L1 expression. We observed a male predominance (P = 0.03), greater use of tobacco (P < 0.001), a higher tumor mutational burden (TMB) (P < 0.001), a higher prevalence of advanced disease (P < 0.001), and a lower prevalence of concurrent targetable driver mutations (P < 0.001) in SMARCA4mut vs SMARCA4wt NSCLCs. Among 513 patients with nonsquamous NSCLC who received immune checkpoint inhibitors, 11% (N = 57) harbored SMARCA4 mutations. From the start of immunotherapy, we observed no difference in overall response rate (ORR 21.5% vs 19.3%; P = 0.3), median progression free survival (mPFS 3.2 months vs 2.1 months; P = 0.4), or median overall survival (mOS 12.0 months vs 8.2 months; P = 0.09) in SMARCA4wt vs SMARCA4mut NSCLC, respectively. However, among KRASmut NSCLC, a concurrent SMARCA4 mut conferred a significantly lower ORR (23.1% vs 0.0%; P = 0.02), a significantly shorter mPFS (4.8 months vs 1.7 month; HR: 0.31 [95% CI: 0.15-0.61]; P < 0.001), and a significantly shorter mOS (15.6 months vs 2.7 months; HR: 0.25 [95%CI: 0.12-0.49]; P < 0.001). The deleterious effect of SMARCA4 mut on immunotherapy outcomes in KRAS mut NSCLC was maintained when controlling for concurrent STK11 mut. Conclusions: SMARCA4 mutations define a genomic subset of NSCLC with unique clinicopathologic characteristics, and confer worse outcomes to immunotherapy in KRAS mut NSCLC.

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16. Checking in with novel cancer therapies: a case of immunotherapy-related large vessel vasculitis

Rheumatology Advances in Practice ◽

10.1093/rap/rkz024 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Yik Long Man ◽

Neil Morton ◽

Begoña Lopez

Keyword(s):

Adverse Events ◽

Steroid Therapy ◽

Immune Checkpoint ◽

Inflammatory Arthritis ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Large Vessel Vasculitis ◽

Large Vessel ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

Abstract Introduction Immune checkpoint inhibition has revolutionised the management of patients with cancer. However, many immunotherapy-related adverse events have been recognised, such as colitis and dermatitis. We are increasingly aware of patients presenting to rheumatology with musculoskeletal complaints including polymyalgia-like symptoms or an inflammatory arthritis. More uncommonly, patients can present with large vessel vasculitis. We present a case of immunotherapy-related large vessel vasculitis following treatment with a combination of ipilimumab and nivolumab. Case description A 67-year-old man has been known to the oncology team with prostate cancer since 2014. He developed osteoblastic metastases despite androgen deprivation therapy and he was subsequently enrolled onto the NEPTUNE study which involved a combination of ipilimumab and nivolumab. Three weeks after his first cycle of immunotherapy, he developed fevers, diarrhoea and a macular rash. He was admitted for a flexible sigmoidoscopy and biopsies demonstrated inflammation in keeping with immunotherapy-related colitis. It was also noted that his thyroxine level was 64.7pmol/L with a TSH of 0.02mlU/L and this was thought to be immunotherapy-related thyroiditis. His immunotherapy was discontinued and he was on a weaning course of prednisolone with a good response. Five months after his single cycle of immunotherapy, he began reporting generalised aches which were worse in his chest and radiated to his right scapula. He also had bilateral shoulder pain but no specific stiffness. This pain was more noticeable as he weaned off the prednisolone. He had no claudication, headaches or constitutional symptoms. A CT pulmonary angiogram showed no evidence of pulmonary emboli, but there was an incidental finding of circumferential thickening of the aorta suggestive of a vasculitis. Inflammatory markers were notably raised - ESR 127mm/h and CRP 199mg/L. There was no evidence of infection on cultures. He was referred to the rheumatology team. Examination was unremarkable with no evidence of weak pulses or bruits. Immunology tests were all negative. An urgent PET-CT was organised which demonstrated extensive active large vessel vasculitis involving the aorta, subclavian, axillary, carotid and vertebral arteries. He was given one dose of methylprednisolone (1mg/kg) which resulted in a marked improvement in his pain overnight. He received two further doses of methylprednisolone and his CRP improved to 38mg/L. He continues to improve on a weaning course of prednisolone. Discussion Ipilimumab was the first checkpoint inhibitor approved for cancer in 2010. Immune checkpoint inhibitors have since become an expanding field in oncology, particularly in resistant or advanced cases of melanoma and lung cancer. There are currently six checkpoint inhibitors licensed by the US Food and Drug Administration. These are monoclonal antibodies targeting the checkpoint pathway including CTLA4, PD-1 and PDL-1. There are well documented case series with regard to immunotherapy-related toxicities including colitis, dermatitis and endocrinopathies. More relevant to rheumatologists, checkpoint inhibitors have also been associated with rheumatic presentations including inflammatory arthritis, polymyalgia rheumatica, sicca symptoms, myositis and vasculitis. A review of the literature in 2018 found 53 cases of vasculitis associated with checkpoint inhibition, of which 20 were confirmed. All these cases were resolved by withholding the immune checkpoint inhibitor and where necessary, giving steroid therapy. On the whole, immunotherapy-related vasculitis is not as common as arthritis or polymyalgia. As the use of checkpoint inhibitors becomes more widespread, it is important that as rheumatologists, we are aware of the various rheumatic conditions that they can trigger and how to manage them. Key learning points This single case highlights the wide range of immunotherapy-related adverse events associated with immune checkpoint inhibition. Their use in clinical practice will likely become more widespread owing to their success in treating a variety of advanced or resistant malignancies. Apart from being familiar with the various rheumatic complaints, we should also be aware of the other systems that can become involved, so that the patient is managed holistically. Symptoms will usually improve with termination of the checkpoint inhibitor but steroid therapy is often required. The addition of disease modifying anti-rheumatic drugs should be considered in cases where there are relapsing symptoms whilst weaning steroids. However, this is a decision that requires a multidisciplinary approach since it could affect the prognosis of the underlying malignancy. With more research into this area, there will a better understanding of the true incidence of immunotherapy-related adverse events in these patients and how to reduce these in the future. Conflict of interest The authors declare no conflicts of interest.

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A phase I/II study of Pexa-Vec oncolytic virus in combination with immune checkpoint inhibition in refractory colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.117 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 117-117

Author(s):

M. Cecilia Monge B. ◽

Changqing Xie ◽

Seth M. Steinberg ◽

Suzanne Fioraventi ◽

Melissa Walker ◽

...

Keyword(s):

Colorectal Cancer ◽

Combination Therapy ◽

Adverse Events ◽

Phase I ◽

Immune Checkpoint ◽

Locally Advanced ◽

Progression Free Survival ◽

Response Analysis ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

117 Background: The benefit of immune checkpoint inhibition is limited to the small percentage of advanced colorectal cancer (CRC) patients whose tumors present mismatch repair (MMR) gene abnormalities; immunotherapy has not shown benefit in patients with MMR proficient CRC. Oncolytic immunotherapy represents a unique therapeutic platform. This phase I trial tests the safety of the combination of pexastimogene devacirepvec (Pexa-Vec) plus durvalumab (durva) in patients with locally advanced or metastatic CRC. Methods: Eligible patients with advanced proficient mixed match repair (pMMR) CRC received intravenous infusion of Pexa-Vec at dose level 3 x 108 plaque forming units (pfu) (DL1) or at 109 pfu (DL2) every 2 weeks for 4 doses and durva 1500 mg every 28 days. Response was assessed with CT every 8 weeks. Adverse events were recorded and managed. The primary endpoint included safety, tolerability and feasibility of this combination therapy. Samples of tumor and peripheral blood were collected for assessment of immune parameters. Results: Sixteen patients (6 males and 10 females) enrolled with a median age of 52.1 years (range 39-69) from Dec, 2017 to Oct, 2018. Four patients were treated with Pexa-Vec at DL1 and durva;twelve patients were treated with Pexa-Vec at DL2 and durva.The most common treatment related adverse events (TRAE) included fever 15/16 (94 %), hypotension 12/16 (75 %), chills 12/16 (75%), fatigue 8/16 (50%), sinus tachycardia 7/16 (44%) and rash 6/16 (38%). Grade 3/4 TRAEs were reported in 8/16 (50%)patients; the most common were fever 7/16 (44 %), lymphopenia 2/16 (13%), neutropenia 1/16 (6%) and anemia 1/16 (6%). 14 patients were evaluable for response analysis; one patient 1/14 (7 %) achieved a confirmed partial response (lasting 7.1 months) and continues to receive treatment, while 13 patients had progressive disease. The median progression free survival (PFS) was 2.2 months (95% CI: 2.2-2.3 months) and the median overall survival (OS) was 7.5 months (CI: 4.9-10.1 months). Conclusions: Combination therapy of Pexa-Vec with durva ICI issafe, well tolerated and demonstrates possible activity in patients with advanced pMMR CRC. Clinical trial information: NCT03206073.

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Stereotactic radiosurgery combined with immune checkpoint inhibition for the treatment of melanoma brain metastases is associated with high levels of extracranial disease control and survivorship - an abscopal effect?

Neuro-Oncology ◽

10.1093/neuonc/noab195.040 ◽

2021 ◽

Vol 23 (Supplement_4) ◽

pp. iv16-iv16

Author(s):

Philip Webb ◽

Mark Zorman ◽

Rhona Watson ◽

Gemma Austin ◽

Carol Thurgood ◽

...

Keyword(s):

Brain Metastases ◽

Immune Checkpoint ◽

Progression Free Survival ◽

Median Number ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Free Survival ◽

Start Date ◽

Melanoma Brain Metastases ◽

Extracranial Disease

Abstract Aims Melanoma brain metastases (MBM) are a common presentation to the neuro-oncology MDT. Stereotactic radiosurgery (SRS) is a highly effective treatment for cerebral metastases, with at least 70% control rates of individual metastases,[1] whilst immune checkpoint blockade has revolutionised the management of metastatic melanoma in recent years.[2] Recent studies have demonstrated that immune checkpoint inhibition alone also has activity in the brain, with MBM response rates of 50% or more.[3, 4] When MBM are treated with combination immunotherapy and SRS together, 12-month intracranial progression free survival (PFS) rates of 85% have been achieved.[4, 5] The aim of the current study was to evaluate the local control of MBM treated at our tertiary referral centre, which benefits from specialist neuro-radiology peer review of SRS contour volumes, and further to investigate whether overall survival is also improved, and what the mechanism of this may be. Method A retrospective analysis of all patients treated with SRS for brain metastases at our teriary SRS centre between June 2017 – January 2020 was performed. Inclusion criteria included patients treated for MBM, who received at least 2 doses of any combination of immune checkpoint inhibition concurrently with (defined as at the time of or commenced within 3 months of) SRS. The primary endpoints were the intracranial and extracranial response rates and survival rate at 12 months. Response was defined as complete response, partial response or stable disease. Secondary endpoints included the rate of imaging-defined radionecrosis, median lesional progression free survival (mPFSlesion), non-lesional intracranial PFS (mPFSintracranial), extracranial PFS (mPFSextracranial) and overall survival (mOS), measured from the start date of SRS to the date of event or censored at the start date of data collection. Kaplan-Meier curves and survival statistics were generated using SPSS v26. Results 33 MBM from 18 patients were identified. The median follow up was 25.8 months (minimum 12 months). Of the 18 patients: the median age was 60 (IQR 48 – 72); 17 (94%) patients were ECOG performance status 0-1; the median number of extracranial disease sites was 2 (pre-immunotherapy) and 1 (pre-SRS); the median duration of immunotherapy treatment was 17.6 (12.9 – 28.5) months, and the median number of metastases treated per patient was 2. Of the 33 metastases: 31 (94%) were supratentorial; 6 (18%) underwent prior neurosurgical resection; the median GTV volume (cc) of unresected metastases was 0.5cc (0.1 – 2.7), and 21 (64%) were treated with single fraction SRS. The median OS and PFS for all subtypes were not reached. The rates of OS, PFSlesion, PFSintracranial and PFSextracranial at 12 months were 93.9%, 87.9%, 81.8% & 75.8% respectively. Conclusion Our cohort of MBM patients appear to perform favourably when compared with the current literature. When compared to a recent extensive systematic review of modern management of MBM, our lesional control rate is as good as the weighted average of concurrent SRS + immunotherapy studies (87.9% vs 85.4% 12-month PFS), however we demonstrate a significantly improved 12-month OS rate (93.9% vs 52.8%) compared to the same (mOS of 15.8 – 17.4 months in other studies).[6,7] Our extra-lesional PFS is high and, compared to extracranial PFS rates from 51% at 6-months to 70.4% at 9-months in the literature,[3,4] our 75.8% control at 12 months suggests that extracranial control could drive the OS benefit. This suggests a benefit of SRS beyond the local control of MBM and questions whether patients without brain metastases may benefit from body SABR to extracranial metastases, to elicit a similar, potentially abscopal type effect.

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Immune Checkpoint Inhibitors in AML-A New Frontier

Current Cancer Drug Targets ◽

10.2174/1568009620666200421081455 ◽

2020 ◽

Vol 20 (7) ◽

pp. 545-557

Author(s):

Rohit Thummalapalli ◽

Hanna A. Knaus ◽

Ivana Gojo ◽

Joshua F. Zeidner

Keyword(s):

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Immune Dysfunction ◽

Cytotoxic Chemotherapy ◽

Immune Checkpoints ◽

Clinical Activity ◽

Cell Mediated Immunity ◽

Hypomethylating Agents ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

Despite recent therapeutic advancements, acute myeloid leukemia (AML) remains a challenging clinical entity with overall poor outcomes. Given the evident role of T cell-mediated immunity in response to allogeneic stem cell transplantation and donor lymphocyte infusions, strategies that enhance immune activation and mitigate immune dysfunction represent attractive therapeutic platforms to improve clinical outcomes in AML. Pre-clinical data suggest that immune dysfunction is a major contributor to AML progression and relapse. Increased expression of immune checkpoints such as programmed death 1 (PD-1) contributes to AML immune evasion and is associated with disease progression. Immune checkpoint inhibition is being explored in AML with early evidence of clinical activity, particularly in combination with cytotoxic chemotherapy and hypomethylating agents. In this review, we explore the scientific rationale behind the use of immune checkpoint inhibition either as single agents or in combination with hypomethylating agents or cytotoxic chemotherapy and provide a clinical update of both completed and ongoing trials in AML.

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Immune Checkpoint Inhibition and the Prevalence of Autoimmune Disorders Among Patients With Lung and Renal Cancer

Cancer Informatics ◽

10.1177/1176935117712520 ◽

2017 ◽

Vol 16 ◽

pp. 117693511771252 ◽

Cited By ~ 9

Author(s):

Sherif M El-Refai ◽

Joshua D Brown ◽

Esther P Black ◽

Jeffery C Talbert

Keyword(s):

Autoimmune Diseases ◽

Renal Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

International Classification Of Diseases ◽

Autoimmune Disorders ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Autoimmune Condition

Purpose: Immune checkpoint inhibition reactivates the immune response against cancer cells in multiple tissue types and has been shown to induce durable responses. However, for patients with autoimmune disorders, their conditions can worsen with this reactivation. We sought to identify, among patients with lung and renal cancer, how many harbor a comorbid autoimmune condition and may be at risk of worsening their condition while on immune checkpoint inhibitors such as nivolumab and pembrolizumab. Methods: An administrative health care claims database, Truven MarketScan, was used to identify patients diagnosed with lung and renal cancer from 2010 to 2013. We assessed patients for diagnosis of autoimmune diseases 1 year prior to or after diagnosis of cancer using International Classification of Diseases, Ninth Revision codes for 41 autoimmune diseases. Baseline characteristics and other comorbid conditions were recorded. Results: More than 25% of patients with both lung and renal cancer had a comorbid autoimmune condition between 2010 and 2013 and were more likely to be women, older, and have more baseline comorbidities. Conclusions: This population presents a dilemma to physicians when deciding to treat with immune checkpoint inhibitors and risk immune-related adverse events. Future evaluation of real-world use of immune checkpoint inhibitors in patients with cancer with autoimmune diseases will be needed.

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Immune-related intestinal pseudo-obstruction associated with nivolumab treatment in a lung cancer patient

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155217738325 ◽

2017 ◽

Vol 25 (2) ◽

pp. 487-491 ◽

Cited By ~ 10

Author(s):

Georgios Fragulidis ◽

Eirini Pantiora ◽

Vasiliki Michalaki ◽

Elissaios Kontis ◽

Elias Primetis ◽

...

Keyword(s):

Lung Cancer ◽

Adverse Effects ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

High Dose ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Gradual Improvement ◽

Organ Systems

Immune checkpoint inhibition therapy using targeted monoclonal antibodies is a new therapeutic approach with significant survival benefit for patients with several cancer types. However, their use can be associated with unique immune-related adverse effects as a consequence of impaired self-tolerance due to loss of T-cell inhibition via a nonselective activation of the immune system. Nivolumab is an anti-PD-1 immune checkpoint inhibitor that was recently developed for cancer immunotherapy with remarkable responses in nonsmall cell lung cancer patients. We present a 62-year-old Caucasian male with recurrent lung adenocarcinoma and currently under third-line therapy with nivolumab, who was admitted in our hospital with abdominal distension. Radiologic findings were consistent with small bowel ileus. After four days of conservative treatment, the patient underwent exploratory laparotomy where no cause of ileus was discovered. Postoperative the ileus persisted and considering that an adverse effect of the immune checkpoint inhibition therapy occurred, the patient received high-dose prednisone resulting in gradual improvement of symptoms. Immune checkpoint inhibitors may induce adverse effects to unaffected organ systems and tissues including the skin, gastrointestinal, hepatic, pulmonary, and endocrine system. The mainstay treatment consists of immunosuppression with corticosteroids in the majority of cases. As the clinical use of immune checkpoint inhibitors is expanding rapidly, there is an emergence of unique immune-related adverse effects in a growing patient population. Gaining early awareness is essential in these patients in order to ensure prompt diagnosis and management.

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Immune Checkpoints as Promising Targets for the Treatment of Idiopathic Pulmonary Fibrosis?

Journal of Clinical Medicine ◽

10.3390/jcm8101547 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1547 ◽

Cited By ~ 2

Author(s):

JanWillem Duitman ◽

Tom van den Ende ◽

C. Arnold Spek

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Immune Checkpoints ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

General Role ◽

Checkpoint Proteins ◽

Immune Checkpoint Proteins

Idiopathic pulmonary fibrosis is a rare, progressive and fatal lung disease which affects approximately 5 million persons worldwide. Although pirfenidone and/or nintedanib treatment improves patients’ wellbeing, the prognosis of IPF remains poor with 5-year mortality rates still ranging from 70 to 80%. The promise of the anti-cancer agent nintedanib in IPF, in combination with the recent notion that IPF shares several pathogenic pathways with cancer, raised hope that immune checkpoint inhibitors, the novel revolutionary anticancer agents, could also be the eagerly awaited ground-breaking and unconventional novel treatment modality limiting IPF-related morbidity/mortality. In the current review, we analyse the available literature on immune checkpoint proteins in IPF to explore whether immune checkpoint inhibition may be as promising in IPF as it is in cancer. We conclude that despite several promising papers showing that inhibiting specific immune checkpoint proteins limits pulmonary fibrosis, overall the data seem to argue against a general role of immune checkpoint inhibition in IPF and suggest that only PD-1/PD-L1 inhibition may be beneficial.

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Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management

ESMO Open ◽

10.1136/esmoopen-2017-000278 ◽

2018 ◽

Vol 3 (1) ◽

pp. e000278 ◽

Cited By ~ 87

Author(s):

Marnix H Geukes Foppen ◽

Elisa A Rozeman ◽

Sandra van Wilpe ◽

Cindy Postma ◽

Petur Snaebjornsson ◽

...

Keyword(s):

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Death Receptor ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Histological Features ◽

Mayo Score ◽

Severity Scores ◽

Anticancer Treatment ◽

Grade 3

BackgroundImmune checkpoint inhibitors are successfully introduced as anticancer treatment. However, they may induce severe immune-related adverse events (irAEs). One of the most frequent irAEs is diarrhoea. The main objective of this study was to analyse symptoms (ie, grade of diarrhoea), endoscopic and histological features and response to management in immune checkpoint inhibition-related colitis (IRC).Patients and methodsWe retrospectively analysed patients who developed diarrhoea on checkpoint inhibition and therefore underwent an endoscopy and/or were treated with corticosteroids. Patients were treated between August 2010 and March 2016 for metastatic melanoma or non-small cell lung cancer. Severity of IRC was scored using the endoscopic Mayo score and the van der Heide score.ResultsOut of a cohort of 781 patients, 92 patients were identified who developed diarrhoea and therefore underwent an endoscopy and/or were treated with corticosteroids. Patients were treated with monotherapy anticytotoxic T-lymphocyte antigen-4, antiprogrammed death receptor-1 or a combination of both. All patients had symptoms of diarrhoea (grade 1: 16%; grade 2: 39% and grade 3: 44%). A complete colonoscopy was performed in 62 (67%) patients, of whom 42 (68%) had a pancolitis (≥3 affected segments). Ulcers were seen in 32% of endoscopies. There was no significant correlation between the grade of diarrhoea at presentation and endoscopic severity scores, the presence of ulcers or histological features. In 54 episodes of diarrhoea (56%), patients received one or more cycles infliximab for steroid-refractory colitis. Patients with higher endoscopic severity scores, ulcers and/or a pancolitis needed infliximab more often.ConclusionsThe correlation between grade of diarrhoea and endoscopic or histological features for severity of colitis is poor. Patients with higher endoscopic severity scores, ulcers or a pancolitis needed the addition of infliximab more often. Therefore, endoscopy may have value in the evaluation of the severity of IRC and may help in decision making for optimal management.

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Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer

10.1101/234906 ◽

2017 ◽

Cited By ~ 1

Author(s):

Valeria Quaranta ◽

Carolyn Rainer ◽

Sebastian R. Nielsen ◽

Meirion Raymant ◽

Muhammad Shamsher Ahmed ◽

...

Keyword(s):

Pancreatic Cancer ◽

T Cell ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Tumour Microenvironment ◽

Ductal Adenocarcinoma ◽

Metastatic Tumour ◽

Metastatic Progression ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

AbstractThe ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumour microenvironment that suppresses and/or excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immuno-protective role of the metastatic tumour microenvironment in pancreatic cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Mechanistically, we find that granulin expression by macrophages is induced in response to colony stimulating factor-1. Genetic depletion of granulin reduces the formation a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumours are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin depleted tumours restored the anti-tumour immune defence and dramatically decreased metastatic tumour burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumours, which are refractory to immune checkpoint inhibitors, into tumours that respond to immune checkpoint inhibition therapies.

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