S c i e n t i f i c A n n u a l R e p o r t 2 0 1 6 Scientific Annual Report 2016 Netherlands Cancer Institute Plesmanlaan 121 1066 CX Amsterdam The Netherlands www.nki.nl Contents 2 Introduction 12 Board members Director of Research 26 Group leaders 16 Neil Aaronson 54 Jacqueline Jacobs 92 Arnoud Sonnenberg 18 Reuven Agami 56 Kees Jalink 94 Hein te Riele 20 Roderick Beijersbergen 58 Jos Jonkers 96 Uulke van der Heide 22 Jos Beijnen 60 Pia Kvistborg 98 Michiel van der Heijden 26 André Bergman 62 Sabine Linn 100 Lonneke van der Poll 28 René Bernards 64 Rene Medema 102 Wim van Harten 30 Anton Berns 66 Gerrit Meijer 104 Flora van Leeuwen 32 Christian Blank 68 Wouter Moolenaar en Matti Rookus 34 Eveline Bleiker 70 Daniel Peeper 108 Fred van Leeuwen 36 Jannie Borst 72 Anastassis Perrakis 110 Maarten van Lohuizen 38 Piet Borst 74 Sven Rottenberg 112 Bas van Steensel 40 Thijn Brummelkamp 76 Sanne Schagen 114 Marcel Verheij 42 Karin de Visser 78 Jan Schellens 116 Emile Voest 44 Elzo de Wit 82 Alfred Schinkel 118 Jelle Wesseling 46 John Haanen 84 Marjanka Schmidt 120 Lodewyk Wessels 48 Michael Hauptmann 86 Ton Schumacher 122 Lotje Zuur 50 Metello Innocenti 88 Titia Sixma 124 Wilbert Zwart 52 Heinz Jacobs 90 Jan-Jakob Sonke 128 Division of 154 Division of 168 Division of Diagnostic Oncology Medical Oncology Radiation Oncology 188 Division of 204 Biometrics 212 Research Surgical Oncology Department facilities 214 Education in 220 Clinical 246 Invited oncology trials speakers 248 Research 268 Personnel projects index Scientific Annual Report 2016 Introduction I am pleased to present our Scientific Annual Report that contains an overview of Director of Research the scientific achievements of the Netherlands Cancer Institute in 2016. More René Medema background information on our research programs and principle investigators can be found on our website (www.nki.nl) or in our Scientific Brochure that is available for download on our website. The Netherlands Cancer Institute is a Comprehensive Cancer Center, and the only Dutch center to officially carry this title. We combine a dedicated cancer hospital and cancer research institute in a single organization. Our hospital currently has 205 beds, 12 state of the art operation theatres, an outpatient clinic with more than 100.000 visits a year, a large radiotherapy department and an extensive infrastructure for clinical research that includes clinical data management and a large array of diagnostic facilities. Over the years, the hospital has built a large repository of patient data and a large collection of tumor and normal tissues. Our clinical research spans across medical, surgical and diagnostic oncology, radiotherapy, pharmacology, epidemiology, psychosocial oncology and research into cost effectiveness of health care and efficiency of planning and organization. Our hospital has seen steady growth in patient numbers over the last years, with an average annual growth of 5%. To accommodate this growth, we have in recent years been expanding. Our building activities have increased the capacity of our outpatient clinic and intensive care, as well as the number of operation rooms. In 2016, our new Pathology wing was finalized. It contains brand new laboratories to accommodate our rapidly expanding pathology facilities. The construction of the building that will house our new Center for Survivorship and Supportive Care was also finalized in 2016. It will become operational during the course of 2017. To continue to accommodate our growth, we will need to plan additional expansions of our clinical capacity. We foresee that new building activities (in addition to the ones that are currently ongoing) will be required from 2018 onwards. One of the biggest changes that took place in 2016 was that Marien van der Meer took the place of Wim van Harten as our new financial director. Wim van Harten left our institute at the end of 2015, after serving in our Board of Directors for almost 15 years. I am confident that in Marien van der Meer we have found a worthy successor. We managed to end 2016 with a profit for the hospital. But the sustained growth in numbers of patients that come to our hospital continues to put a strain on our system. Our excellent reputation is attracting more patients than we can possibly treat due to limitations in physical space and personnel. This, combined with tighter budgets from health insurance companies, are putting an increasing strain on all of our activities. Our clinical research program suffers from the limited time that clinicians can dedicate to research. Thus, an important challenge for our institute will be to allocate sufficient time to our clinician researchers to be able to continue to develop better treatments and provide the evidence that is necessary to make these new treatment options available to patients throughout the Netherlands. We continue to see a growth in the number of clinical studies in our Institute that are based on research performed at the NKI (tables 2 and 3). We want to continue to support this important development, essential for the improvement of cancer therapies, but this will require additional funding capacity. In 2016, we made additional investments in three of our research themes, molecular oncology, immunotherapy and Image-guided interventions, but maintaining an international competitive program requires continuous investments in infrastructure, and it is challenging for us to find sufficient funding for this. Also, we run many projects that produce very large datasets, but the long-term maintenance of these valuable resources requires extensive management and storage costs. These challenges become ever more difficult for us to overcome due to the fact that our research program is in 2 the largest part financed from project (short-term) funding. We are very thankful to the Dutch Ministry of Health, Welfare and Sport and to the Dutch Cancer Society (KWF Kankerbestrijding) for their generous institutional funding (table 1). However, our funding ratio has steadily shifted towards external grants, donations and short-term research agreements with third parties. Currently ~65% of our total research budget comes from such sources, making it challenging to maintain sufficient manpower in the underlying infrastructure. HIGHLIGHTS It is impossible to provide a complete overview of the total impact generated by our institute in 2016 in this introduction. Many of the highlights can be found in reports of the individual group leaders further on in this annual report and on our website. I have chosen to mention a few highlights of our 5 research themes here. Molecular Oncology The lab of Reuven Agami developed a technique to detect metabolic vulnerabilities of tumors, called DIRICORE. Postdoc Fabricio Loayza-Puch was one of the main inventors of this new technique, and was awarded with the AVL prize for his groundbreaking work. DIRICORE could lead to a whole new approach of fighting cancer based on exploiting the specific amino acid requirements of individual tumors. Joris van Arensbergen and colleagues in the lab of Bas van Steensel developed an ultra-high throughput method to assay the transcriptional activity of more than 100 million DNA fragments in a single experiment. This new approach will help to unravel how gene expression is controlled in different cell types and in response to various signals. In the department of Cell Biology, Wouter Molenaar’s group found that the glycerophosphodiesterase GDE2 promotes neuroblastoma differentiation and is a marker of the clinical outcome. An important discovery, because little is still known about this type of childhood cancer. Femke Feringa, together with other members of my lab, showed that the cellular response to DNA damage is dramatically different in cells that are about to undergo cell division. Her work demonstrated that the capacity to recover from a DNA damaging insult is lost as cells progress through the division cycle. This discovery could help to improve the efficacy of DNA damaging therapies. TABLE 1 CORE RESEARCH FUNDING THE NETHERLANDS CANCER INSTITUTE - ANTONI VAN LEEUWENHOEK HOSPITAL BY THE DUTCH CANCER SOCIETY AND THE MINISTRY OF HEALTH, WELFARE AND SPORT IN THE PERIOD 2005 – 2016 IN MILLION EUROS. 30 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 25 20 15 10 5 0 DUTCH CANCER SOCIETY MINISTRY OF HEALTH, WELFARE & SPORT* TOTAL * EXCLUDED ARE THE REIMBURSEMENT FOR INTEREST AND DEPRECIATION OF BUILDINGS 3 TABLE 2 THERAPEUTIC CONCEPTS THAT ARE THE PRODUCT OF FUNDAMENTAL AND TRANSLATIONAL RESEARCH PERFORMED AT THE NETHERLANDS CANCER INSTITUTE, AND CURRENTLY IN CLINICAL DEVELOPMENT IN OUR INSTITUTE REFERENCE CLINICALTRIALS. AVL CODE NOVEL TREATMENT TUMOR TYPE NUMBER** GOV 1 NCT01719380 M12LGX EGFRi + BRAFi ± PI3Ki Mutant BRaf Colorectal Cancer 1 NCT01750918 M13DPT EGFRi + BRAFi ± MEKi Mutant BRaf Colorectal Cancer 2 NCT02039336 M13DAP Pan-HERi + MEKi Mutant KRas Colorectal Cancer 2 NCT02230553 M14LTK Pan-HERi + MEKi Mutant KRas Colorectal Cancer 3-5 Registration M14REV Carboplatin + PARPi Advanced Breast Cancer with pending BRCA mutation 6,7 NCT02285179 M14POS Tamoxifen + PI3Ki ER/PR+ and HER2- Breast Cancer 8-10 NCT01057069 M09TNM Neo-adjuvant Chemo Triple-Negative Breast Cancer 8-15 NCT01898117 M13TNB Paclitaxel ± VEGFi BRCA1-like Breast Cancer 16,17 NTC02278887 M14TIL TIL vs. Ipilimumab Metastatic Melanoma 18-20 NCT00407186 M06CRI Chemoradiotherapy + surgery Resectable Gastric Cancer 21 NCT02229656 N13ORH Radiotherapy + PARPi Laryngeal and HPV-Negative Oropharyngeal SCC 21 NCT01562210 N11ORL Radiotherapy ± Cisplatin + Locally Advanced NSCLC PARPi 21 NCT02227082 N13ORB Radiotherapy + PARPi Locally Advanced Triple-Negative Breast Cancer 22 NCT01504815 M11ART Cisplatin + Adaptive High Dose Locally Advanced Oropharynx, Oral Radiotherapy Cavity or Hypopharynx SCC 23 *NCT01024829 M09PBO FDG-PET-based Boosting RT Inoperable NSCLC 24 NCT01780675 M12PHA Hippocampus Avoidance PCI SCLC 25 NCT01933568 N12HYB Combined Stereotactic and Stage II-III NSCLC Conventional Fractionated RT 26 *NCT01543672 M11VOL MLD-based SBRT Inoperable + Peripheral NSCLC 27 NCT01024582 M08PBI Partial Accelerated Early Stage Operable Breast Preoperative Irradiation Cancer 28,29 NCT00582244 P07CB Cognitive Behavioral Therapy & Breast Cancer Physical exercise 30 NCT00783822 P08TIM Rapid Genetics BRCA mutant Breast Cancer 31,32 NCT015622431 P11SIG Problem checklist Breast & Colon Cancer REFERENCE NTR CODE AVL CODE NOVEL TREATMENT TUMOR TYPE NUMBER 33 *NTR4607 N14HPV DNA vaccination HPV16+ Vulvar Neoplasia 34 NTR3539 M11TCR MART-1 TCR gene therapy Metastatic Melanoma 35 NTR2159 P09PHY Physical Exercise Breast & Colon Cancer 37 M15CRI Preoperative chemo vs Resectable gastric cancer chemoradiotherapy vs chemo + chemoradiotherapy 38 M15PAP Pre- vs postoperative Early stage breast cancer accelerated partial breast irradiation 39 M16HFL Hypofractionated focal Prostate cancer ablative radiotherapy * THERAPEUTIC CONCEPT NOT SOLELY, BUT PRIMARILY DEVELOPED AT THE NETHERLANDS CANCER INSTITUTE ** SEE REFERENCE ON THE NEXT PAGE 4 1. Prahallad A et al. Unresponsiveness 12. Wessels LF et al. Molecular 23. Van Kesteren Z et al. A practical 34. Gomez-Eerland R et al. Manufacture of colon cancer to BRAF(V600E) classification of breast carcinomas by technique to avoid the hippocampus in of gene-modified human T-cells with inhibition through feedback activation comparative genomic hybridization: prophylactic cranial irradiation for lung a memory stem/central memory of EGFR. Nature 2012;483:100-3 a specific somatic genetic profile cancer. Radiother Oncol. 2012;102:225-7 phenotype. Hum GeneTher Methods. for BRCA1 tumors. Cancer Res 2014;25:277-87 2. Sun C et al. Intrinsic resistance to 2002;62:7110-7117 24. Grills IS et al. A collaborative MEK inhibition in KRAS mutant lung and analysis of stereotactic lung 35. de Vos van Steenwijk PJ et al. colon cancer through transcriptional 13. van Beers EH et al. Comparative radiotherapy outcomes for early-stage The long-term immune response induction of ERBB3. Cell Rep. genomic hybridization profiles in human non-small-cell lung cancer using after HPV16 peptide vaccination 2014;7:86-93 BRCA1 and BRCA2 breast tumors daily online cone-beam computed in women with low-grade pre- highlight differential sets of genomic tomography image-guided radiotherapy. malignant disorders of the uterine 3. Rottenbwerg S et al. High sensitivity aberrations. Cancer Res 2005;65:822- J Thorac Oncol. 2012;7:1382-93 cervix: a placebo-controlled phase II of BRCA1-deficient mammary tumors to 827 study. Cancer Immunol Immunother. the PARP inhibitor AZD2281 alone and in 25. Peulen H et al. Mid-ventilation 2014;63:147-60 combination with platinum drugs. Proc. 14. Joosse SA et al. Prediction of based PTV margins in Stereotactic Natl. Acad. Sci. USA 2008;105:17079-84 BRCA1-association in hereditary Body radiotherapy (SBRT): a 36. van Waart H et al. Effect of low non-BRCA1/2 breast carcinomas with clinical evaluation. Radiother Oncol. intensity physical activity and high 4. Fong PC et al. Inhibition of poly(ADP- array-CGH. Breast Cancer Res Treat 2014;110:511-6 intensity physical exercise during ribose) polymerase in tumors from 2009;116: 479-489. adjuvant chemotherapy on physical BRCA mutation carriers. N Engl J Med. 26. Van der Leij F et al. Target volume fitness, fatigue and chemotherapy 2009;361:123-34 15. Lips EH et al. Quantitative copy delineation in external beam partial completion rates: Results of the PACES number analysis by Multiplex Ligation- breast irradiation: less inter-observer randomized clinical trial. J Clin Oncol 5. Oonk AM et al. Clinical correlates dependent Probe Amplification (MLPA) variation with preoperative- compared 2015;33:1918-27 of 'BRCAness' in triple-negative of BRCA1-associated breast cancer to postoperative delineation. Radiother breast cancer of patients receiving regions identifies BRCAness. Breast Oncol. 2014;110:467-70 37. Trip AK et al. Preoperative adjuvant chemotherapy. Ann Oncol. Cancer Res 2011;13:R107 chemoradiotherapy in locally advanced 2012;23:2301-5 27. Kenter GG et al. Vaccination gastric cancer, a phase I/II feasibility 16. Kvistborg P et al. TIL therapy against HPV-16 oncoproteinsfor vulvar and efficacy study. Radiother Oncol. 6. Beelen K et al. PIK3CA mutations, broadens the tumor-reactive CD8(+) T intraepithelial neoplasia. N Engl J Med. 2014;112: 284-8 phosphatase and tensin homolog, cell compartment in melanoma patients. 2009;361:1838-47 human epidermal growth factor Oncoimmunology 1:409-418 38. Van der Leij F et al. Target volume receptor 2, and insulin-like 28. Duijts SFA et al. Efficacy of delineation in external beam partial growth factor 1 receptor and 17. Dikken JL et al. Neo-adjuvant cognitive behavioral therapy and breast irradiation: less inter-observer adjuvant tamoxifen resistance in chemotherapy followed by surgery physical exercise in alleviating variation with preoperative- compared postmenopausal breast cancer and chemotherapy or by surgery and treatment-induced menopausal to postoperative delineation. Radiother patients. Breast Cancer Res. chemoradiotherapy for patients with symptoms in patients with breast Oncol. 2014;110: 467-70 2014;16:R13 resectable gastric cancer (CRITICS). cancer: Results of a randomized BMC Cancer 2011;11:329 controlled multicenter trial. J Clin Oncol 39. Lips IM et al. Single blind 7. Beelen K et al. Phosphorylated 2012;30:4124-33 randomized phase III trial to investigate p-70S6K predicts tamoxifen resistance 18. Trip AK et al. Preoperative the benefit of a focal lesion ablative in postmenopausal breast cancer chemoradiotherapy in locally advanced 29. Mewes JC et al. 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An aCGH in combination with radiotherapy to in newly diagnosed breast cancer classifier derived from BRCA1-mutated improve cancer treatment: Rationale, patients: Findings from a randomized breast cancer and benefit of high-dose mechanisms of action and clinical controlled trial. Br J Cancer platinum-based chemotherapy in HER2- perspective. Drug Resist Updat 2014;110:1081-7 negative breast cancer patients. Ann 2010;13:29-43 Oncol. 2011; 22:1561-70 31. Eijzenga W et al. Effect of 21. Heukelom J et al. Adaptive and routine assessment of specific 10. Vollebergh MA et al. Genomic innovative Radiation Treatment FOR psychosocial problems on personalized patterns resembling BRCA1- and improving Cancer treatment outcomE communication, referrals and distress BRCA2-mutated breast cancers predict (ARTFORCE); a randomized controlled levels in cancer genetic counseling benefit of intensified carboplatin-based phase II trial for individualized practice: A randomized controlled trial. chemotherapy. Breast Cancer Res. treatment of head and neck cancer. J Clin Oncol. 2014;32:2998-3004 2014;16:R47 BMC Cancer 2013;13:84 32. Eijzenga W et al. Routine 11. Rottenberg S et al. Impact of 22. Van Elmpt W et al. The PET-boost assessment of psychosocial problems intertumoral heterogeneity on randomised phase II dose-escalation after cancer genetic counseling: predicting chemotherapy response of trial in non-small cell lung cancer. Results from a randomized controlled BRCA1-deficient mammary tumors. Radiother Oncol. 2012;104:67-71 trial. Clin Genetics 2015;87:419-27 Cancer Res 2012; 72: 2350-2361 33. Bins AD et al. A rapid and potent DNA vaccination strategy defined by in vivo monitoring of antigen expression. Nat Med. 2005;11:899-904 5 The group of Heinz Jacobs demonstrated that open chromatin configuration is a primary risk-determinant for chromosome translocations. Thomas van Ravesteyn, Marleen Dekker and Hellen Houlleberghs from the Te Riele group developed a method for high-throughput oligonucleotide-directed mutation screening (ODMS) which will be very useful to distinguish mutants of DNA mismatch repair genes that are of clinical significance versus others that are not. Michela Serresi and colleagues (Van Lohuizen group) demonstrated that loss of the Polycomb repressor complex2 (PRC2) can promote inflammation and reduce tumor growth in KRAS-driven non-small cell lung cancer that have retained wildtype p53, while it promotes a switch to a highly aggressive mutinous adenocarcinoma via an epithelial- mesenchymal transition (EMT) in this tumor type when p53 is mutated. Willem-Jan Keune from the lab of Anastassis Perrakis has discovered the function of the elusive ‘tunnel’ structure in autotaxin, an enzyme that is involved in numerous cell signaling processes, including cell proliferation and cell migration. It turns out that certain natural steroids can bind inside this tunnel and thus inhibit the function of the enzyme. It was the first time a natural regulator for the activity of autotaxin was discovered. The discovery provides a molecular explanation for the therapeutic effect of bile salt based drugs, but also has several other potential clinical implications. Jacqueline Staring, a member of the laboratory of Thijn Brummelkamp, has discovered that once picornaviruses are attached to the cell a single human host cell protein assists their further entry. The discovery of this common host factor, the lipid-modifying enzyme PLA2G16, offers promise for future antiviral therapies against this large family of viruses, that cause diseases such as polio, infections of the heart, meningitis, hepatitis and the common cold. Brummelkamp’s lab previously discovered that the Ebola and Lassa viruses also rely on a two-step mechanism to infect cells, including a receptor on the cell surface as well as one inside of the cell. Personalized treatment In 2016, the final conclusions of the MINDACT study were published. In this large-scale, long-term European study, the reliability of the 70-gene signature test for breast cancer patients (also known as the MammaPrint) was evaluated. The MammaPrint was invented around a decade ago by NKI researchers Laura van ‘t Veer and René Bernards. It can classify hormone-sensitive early stage breast tumors as ‘low risk’ or ‘high risk’ when it comes to the possibility of developing metastases. MINDACT has provided the highest level of clinical evidence of the test’s reliability. This means it can safely and reliably be used in the clinic to determine which women with breast cancer need additional chemotherapy and which do not, an issue that is relevant for as much as 2000 women per year in the Netherlands alone. Loredana Vecchione and Valentina Gambino from the group of René Bernards showed that a subset of colon cancers is exquisitely sensitive to the microtubule poison vinorelbin. They showed that this subset has a characteristic gene signature, also known as “B-Raf”-like tumors, implying that vinorelbin is a potential tailored treatment for B-Raf-like colon cancers. The lab of Jan Schellens published the results of a clinical trial that shows how a new type of anti-cancer drug, currently known by the name AZD1775, can enhance the effect of existing chemotherapeutic drugs. It shuts down the G2 phase of cell division, so DNA damage that is induced by the chemotherapeutics cannot be repaired. Of 23 women with advanced ovarian cancer who at first did not respond to classic chemotherapeutics and whose tumors harbored a p53 mutation, 43% had benefit from the combination of chemotherapy with AZD1775. They lived much longer than they would have without the drugs, and two of the patients have survived for six years now. Also, Maarten Deenen in the group of Jan Schellens obtained evidence that upfront genotyping of patients for dihydropyrimidine dehydrogenase (DPD) activity and dose-adaptation significantly improves safety of fluoropyrimidine therapy and is cost-effective. Suzan Stelloo from the labs of Wilbert Zwart and André Bergman revealed a surprising favorable prognosis in primary prostate cancer patients with activated mTOR pathway, providing a clinical rationale why neoadjuvant mTOR inhibitor treatment in prostate cancer is unsuccessful. Daniel Vis of the lab of Lodewyk Wessels has shown that patient-derived cancer cell lines harbor most of the same genetic changes found in patients’ tumors. This means they can indeed be used to learn how tumors are likely to respond to new drugs, increasing 6 the success rate for developing new personalized cancer treatments. In his systematic, large-scale study, Vis combined molecular data from 11.000 tumors and cancer cell lines with drug sensitivity measurements. Also from the Wessels’ lab, Ewald van Dyk spearheaded the development of a new algorithm called RUBIC, to detect aberrations in DNA copy number data sets. RUBIC performs better than two of the existing state- of-the-art approaches to detect these aberrations, that can be used for cancer driver gene discovery. The Jonkers lab managed to develop a technique to create mouse models for invasive lobular carcinoma that doesn’t require lengthy breeding of transgenic mice. His lab also discovered two previously unidentified ways in which breast tumors can harbor resistance against cisplatin and PARP-inhibitors. In turns out that if the protein that is produced by BRCA1 lacks a characteristic RING-domain, cancer cells don’t respond to these two drugs. Next to this they found that certain epigenetic changes in the regulation of BRCA1 can cause acquired drug resistance. To broaden the perspectives of melanoma patients, the groups of Peeper, Haanen, Schumacher and Blank established a large collection of patient-derived xenografts (PDX) and identified a BRAFV600E kinase domain duplication in drug-resistant tumors. Treatment with a new RAF dimerization inhibitor reversed drug resistance, illustrating the utility of this PDX platform and warranting clinical validation of BRAF dimerization inhibitors for this group of melanoma patients. Immunotherapy NKI immunologists Christian Blank, John Haanen and Ton Schumacher proposed a framework that can be used to determine which type of cancer immunotherapy is best for an individual patient: The Cancer Immunogram, that was published in the journal Science. In another paper in Science, Ton Schumacher and his Norwegian colleague Johanna Olweus showed that it is possible to fight cancer with the help of ‘borrowed’ immune cells. In their proof-of-principle study they found that naïve T cell repertoires of healthy blood donors provide a source of neoantigen-specific T cells. T cells redirected with T cell receptors identified from donor-derived T cells efficiently recognized patient- derived melanoma cells harboring the relevant mutations, providing a rationale for the use of such “outsourced” immune responses in cancer immunotherapy. A team led by Inge Verbrugge and Christian Blank compared several combinations of immunotherapy and radiotherapy in a mouse melanoma model, to see whether these therapies can enhance each other. Their study suggests that a combination of anti-PD-1, anti-CD137 and radiotherapy may be superior to other combinations of immunotherapy and radiotherapy that are currently being tested in human patients. In his OpACIN study, Christian Blank showed the profound anti-tumor activity, but also toxicity, of neo-adjuvant immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies in stage III melanoma patients.  These data underscore the potential value of T cell checkpoint blockade during earlier disease stage. In addition, these data strongly suggest systemic immune suppression as an important factor limiting the activity of T cell checkpoint blockade during later stage disease. Tomasz Ahrends in the group of Jannie Borst demonstrated how CD4 T cell help alters many aspects of CD8 T cell function, and also how CD27 ligation can largely compensate for the lack of T cell help. These data may be used to design strategies to optimally instill desired activities in tumor reactive CD8 T cells that are induced by vaccination.  In a collaboration between the Schumacher, Brummelkamp, and Jannie Borst lab, Riccardo Mezzadra, Chong Sun, and Lucas Jae identified CMTM6 as a protein partner of PD-L1 that influences the expression of PD-L1 on the surface of both tumor cells and myeloid cells.  Based on these data, CMTM6 may be pursued as a potential therapeutic target. Image-guided interventions In March the MRI-linac was installed at the department of Radiation Oncology, marking the beginning of a practice-change in image-guided adaptive radiotherapy. In September the first images were made with the MR-Linac system, while simultaneously irradiating the object. The group of Uulke van der Heide developed and validated a method to generate ‘CT-like’ images from MRI scans of the prostate. This will avoid the need to acquire a planning CT scan for patients who already received an MRI exam for target delineation. This method is currently implemented clinically. 7