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4Th Symposium on Advances in Cancer Immunology and Immunotherapy, November 29–December 1, 2018, Athens, Greece

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4Th Symposium on Advances in Cancer Immunology and Immunotherapy, November 29–December 1, 2018, Athens, Greece Cancer Immunology, Immunotherapy (2019) 68:1391–1400 https://doi.org/10.1007/s00262-019-02364-2 MEETING REPORT 4th Symposium on Advances in Cancer Immunology and Immunotherapy, November 29–December 1, 2018, Athens, Greece Sotirios P. Fortis1 · Athanasios Kotsakis2 · Christophe Le Tourneau3 · Ourania E. Tsitsilonis4 · Vassilis Georgoulias5 · Constantin N. Baxevanis1 Received: 31 March 2019 / Accepted: 2 July 2019 / Published online: 15 July 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Keywords Cancer immunology · Immunotherapy · Biomarkers · Immune monitoring · Immunomodulatory mechanisms Abbreviations NTRK Neurotrophic tropomyosin receptor kinase ALK Anaplastic lymphoma kinase PARP Poly (ADP-ribose) ATF Activating transcription factor pTreg Peripheral Treg BCSC Breast cancer stem cells TEX Tumor-derived exosomes CHOP CCAAT-enhancer-binding protein homologous TIGIT T-cell immunoglobulin and ITIM domain protein TIM-3 T-cell immunoglobulin, mucin domain-3 CPI Checkpoint inhibitor TLS Tertiary lympoid structure EMA European medicines agency TME Tumor microenvironment EML4 Microtubule-associated protein-like 4 TP53 Tumor protein 53 EV Extracellular vesicles Treg T regulatory cells FLIP FLICE-inhibitory protein UPR Unfolded protein response GO Gemtuzumab ozogamicin VLP Virus-like particles GPCRs Protein-coupled receptors HNSCC Head and neck squamous cell carcinoma ICIs Immune checkpoint inhibitors Introduction ICIR Immune checkpoint inhibitory receptor irAEs Immune-related adverse events The 4th symposium on advances in cancer immunology and iTreg Induced regulatory T cell immunotherapy was held from November 29 to December 1, miTRAP miRNA trapping by RNA in vitro afnity 2018, in Athens, Greece. The 4th symposium aimed to bring purifcation together many of the leading researchers and clinicians from MM Multiple myeloma Europe and the US to report on most recent advances in can- NSCLC Non-small cell lung cancer cer immunology and immunotherapy and to promote inter- actions between speakers and participants, thus encouraging * Sotirios P. Fortis stimulating discussions and providing network opportunities [email protected] and new collaborations. The main objectives were to gather, 1 share and exchange current knowledge from the feld of Cancer Immunology and Immunotherapy Center, tumor biology and cancer immunology and immunotherapy, Saint Savas Cancer Hospital, 171 Alexandras avenue, 11522 Athens, Greece and to translate and extend this knowledge to the clinic. The main topics included: (1) immune suppression; (2) innate 2 Department of Medical Oncology, University Hospital of Larissa, Larissa, Thessaly, Greece immunity in cancer; (3) monitoring of immunomodulatory mechanisms; (4) combinational treatment; (5) biomarkers 3 INSERM U900 Research Unit, Department of Drug Development and Innovation (D3i), Institut Curie, for immunotherapy; and (6) clinical trials. Paris-Saclay University, Paris, France 4 Overcoming immune suppression Department of Biology, National and Kapodistrian University of Athens, Athens, Greece 5 1st Department of Medical Oncology, Metropolitan General, The tumor microenvironment (TME) contains a suppres- Athens, Greece sor network which promotes tumor growth, invasion and Vol.:(0123456789)1 3 1392 Cancer Immunology, Immunotherapy (2019) 68:1391–1400 metastasis. Detailed investigation of the immunosuppressor by Theresa L. Whiteside (University of Pittsburgh Cancer circuits within the TME will improve our understanding of Institute, Pittsburgh, USA) on the functional role of regula- tumor biology and evolution and at the same time will ena- tory T cells (Treg) in cancer. Although Treg were discovered ble the design of novel therapeutic modalities against can- more than 20 years ago and have been a subject of intense cer. In this session, Vincenzo Bronte (School of Medicine interest and investigation ever since, many questions about and Surgery, University of Verona, Verona, Italy) provided their origin, development, functions and clinical signifcance an overview of the role of myeloid-derived suppressor cells in cancer remain elusive. No defnitive marker for human (MDSC) in tumor immune evasion. Low doses of diferent Treg has been identifed; the most frequently used mark- chemotherapeutic agents selectively eliminated the mono- ers HELIOS, neuropilin-1 (NRP-1) and CD15s are not spe- cytic-MDSC (M-MDSC) and enhanced the therapeutic ef- cifc for all Treg. Sakaguchi’s classifcation of Treg based cacy of adoptively transferred, tumor-specifc CD8+ T cells. on expression of CD45RA and FOXP3 identifes fraction II His team found that chemotherapeutics afecting M-MDSC Treg (FOXP3 + CD45RAlow) as the true suppressor cells that all shared the ability to modulate the anti-apoptotic protein accumulate in tumors. Strikingly, there exists a lack of clarity FLICE-inhibitory protein (FLIP) both in vitro and in vivo, in interpretation of Treg responses to checkpoint blockade. and that enforced FLIP expression which partially protected Treg that accumulate at tumor sites and in the circulation of the cells from chemotherapy-induced death. Unexpectedly, patients with cancer are referred to as induced Treg (iTreg). FLIP induction in monocytes regulated a complex transcrip- They difer phenotypically and functionally from peripheral tional program, which included several MDSC-related genes Treg (pTreg) and mediate vigorous suppression of immune such as CD274, CD273, IL-10 and IDO1, promoting their cells utilizing a variety of mechanisms. They may or may transition towards fully immune suppressive monocytic- not be FOXP3+ but co-express numerous immune check- MDSC (M-MDSC). To prove the immunoregulatory power point inhibitory receptors (ICIRs), e.g., cytotoxic CTLA- of this molecular axis, they showed that injection of c-FLIP- 4, PD-1, T-cell Ig and mucin domain-containing protein-3 expressing monocytes was able to control GvHD progres- (TIM3), lymphocyte activation gene 3 (LAG3) and T-cell Ig sion in a setting of xenogeneic transplantation. Patients with and ITIM domains (TIGIT). It was, therefore, expected that pancreatic ductal adenocarcinoma presented an increased the suppressor activity of Treg expressing ICIRs would be frequency of cellular FLICE (FADD-like IL-1β-converting silenced following delivery of checkpoint inhibitory Abs that enzyme) inhibitory protein (c-FLIP) + PD-L1 + CD14 + cells block negative signaling. Unexpectedly, responses of Treg to in the blood and the higher circulating levels of these cell immune checkpoint blockade difered from those of efec- subsets together with increased concentrations of plasma tor T cells: while the blockade released all other immune IL-6 correlated with shorter overall survival. Collectively, cell types from suppression and rejuvenated their anti-tumor these data suggest a critical role of c-FLIP in cancer pro- activities, Treg-mediated suppression, phenotype, frequency motion by regulating the immunosuppressive properties of and stability were not reduced. It appears that Treg are resist- mature myeloid cells. Viktor Umansky (German Cancer ant to ICIR blockade with Abs, and it has been suggested Research Center (DKFZ), Heidelberg, Germany) reported that this resistance may underlie unresponsiveness of cancer on the immunosuppressive network in the melanoma micro- patients to immune checkpoint inhibitors (ICIs). A number environment, where MDSC induced by chronic infamma- of questions and controversies about Treg remain, including tion play a major role. The accumulation and activation of their “transcriptional signature,” the nature of the primary MDSC could be mediated not only by soluble infammatory target of Treg, the role of APC in Treg functions, the redun- factors but also by tumor-derived extracellular vesicles (EV). dancy of Treg suppressive mechanisms and the requirement Recent studies from his laboratory showed that EV isolated for overexpression of multiple ICIRs on Treg. Recent data from Ret mouse melanoma cells induced an upregulation of suggest that Treg are functionally highly diverse regulatory PD-L1 on immature myeloid cells, leading them to acquire cells that are involved in a broad spectrum of immune and the ability to suppress T-cell activation. PD-L1 expression non-immune activities in various tissues and organs. In the and the immunosuppressive ability of EV-generated MDSC tumor microenvironment, Treg are subverted by the tumor, were dependent on the interaction between TLR4 on mye- and their immunosuppressive activities represent a major loid cells and HSP86 on EV followed by NF-κB activation. barrier to successful cancer immune therapies. EV from human melanoma cells or plasma of melanoma patients induced PD-L1 upregulation on normal monocytes The role of innate immunity in cancer leading to their conversion into immunosuppressive cells. Thus, these fndings highlight novel mechanisms of MDSC Chemokines and their specific receptors constitute a generation from normal myeloid cells by melanoma EV, sug- complex network within the TME which depending on gesting the importance of EV targeting for tumor therapy. A the context may promote or suppress tumor growth. diferent mechanism of immunosuppression was described 1 3 Cancer Immunology, Immunotherapy (2019) 68:1391–1400 1393 Toll-like receptors (TLR) and their agonists play a sig- burden and provide an adjuvant therapy to standard nifcant role in inducing and/or optimizing anti-tumor treatments. immune pathways. Nathan Karin (Rappaport Faculty of Medicine, Technion-Israel Institute of Technology,
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