David Fruman, USA

Lecture Title: PI3K IN CANCER

“Both immunodeficiency and hyperactivation of the immune system can promote tumorigenesis.”

Please summarize your lecture’s learning objectives.

Attendees will learn how mutations in the PIK3CD and PIK3R1 genes cause immunodeficiency and increase cancer incidence. The audience will also learn how oncology drugs targeting the PI3K pathway can be repurposed to treat immunodeficiency.

Why is this important?

This is important because genome sequencing efforts have shown that a variety of PIDs are linked to mutations in the PI3K signaling pathway.

Please share any recommended reading ahead of the lecture.

• PI3Kδ and primary immunodeficiencies: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291318/ 

Jerome Galon, France

Lecture Title: The Immunology of the Tumor-Microenvironment: Impact on Cancer Progression, Invasion, Recurrence, and Survival of Patient.

Please summarize your lecture’s learning objectives.

My lecture will demonstrate the key role played by pre-existing adaptive immunity against cancer, and how this knowledge can be leveraged to get accurate prognostic information for cancer patients. The importance of the immune system in shaping cancer evolution will be also highlighted.

Why is this important?

Immunotherapy is now revolutionizing Oncology. Understanding of the pre-existing immunity of patients is essential to guide immunotherapy and develop novel combination therapies.

Please share any recommended reading ahead of the lecture.

• Immunoscore®: From the science to the clinical evidence in colon cancer: https://www.openaccessgovernment.org/immunoscore-colon-cancer/63441/
• Evolution of Metastases in Space and Time under Immune Selection. Angelova, M., Mlecnik, B., Vasaturo, A., Bindea, G., Fredriksen, T., Lafontaine, L., . . . Galon, J. (2018). Evolution of Metastases in Space and Time under Immune Selection. Cell, 175(3), 751-765 e716. doi:10.1016/j.cell.2018.09.018
• The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Galon, J., Angell, H. K., Bedognetti, D., & Marincola, F. M. (2013). Immunity, 39(1), 11-26. doi:10.1016/j.immuni.2013.07.008
• Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Galon, J., & Bruni, D. (2019). Nat Rev Drug Discov, 18(3), 197-218. doi:10.1038/s41573-018-0007-y
• Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability. Immunity,  Mlecnik, B., Bindea, G., Angell, H. K., Maby, P., Angelova, M., Tougeron, D., . . . Galon, J. (2016). 44(3), 698-711. doi:10.1016/j.immuni.2016.02.025

Fabian Hauck, Germany

Lecture Title: CARMIL2 Deficiency and EBV Induced Malignancy

Please summarize your lecture’s learning objectives.

The diagnosis of EBV-positive smooth muscle tumors relies on histopathology and immunohistochemistry. EBV-positive smooth muscle tumors present in the context of combined immunodeficiency and a curative treatment strategy should include allogeneic hematopoietic cell transplantation.

Why is this important?

Smooth muscle tumors are only infrequently analyzed for the presences of EBV and the suspicion of an underlying primary immunodeficiency is not always raised.

Please share any recommended reading ahead of the lecture.

• Intrinsic and Extrinsic Causes of Malignancies in Primary Immunodeficiency Disorders. Hauck F, Voss R, Urban C, Seidel MG. J Allergy Clin Immunol.2018Jan;141(1):59-68.e4.
• A human immunodeficiency syndrome caused by mutations in CARMIL2. Nat Commun. 2017 Jan 23;8:14209.
• Epstein-Barr Virus+ Smooth Muscle Tumors as Manifestation of Primary Immunodeficiency Disorders. Magg T, Schober T, Walz C, Ley-Zaporozhan J, Facchetti F, Klein C, Hauck F. Front Immunol. 2018Feb 27;9:368. 

SERGIO D. ROSENZWEIG, USA

Ikaros in PID: A Diverse Field

Please summarize your lecture’s learning objectives.

In the last 3 years, mono-allelic germline defects in IKAROS acting through alternative pathophysiologic mechanisms (i.e., haploinsufficiency or dominant negative) have been reported to cause CVID or CID. Novel, and yet unreported allelic variants acting through different than the above-mentioned mechanisms, are associated with phenotypes primarily identified by immune dysregulation, cytopenias and a broader range of hematologic malignancies.

Why is this important?

Somatic mutations in IKAROS were originally reported as poor predictor factors in paediatric patients with B-ALL. In 2018, germline mutations in IKAROS, as the ones described in patients with primary immunodeficiency, were linked to almost 1% of all B-ALLs, the most common malignancy in paediatrics.

Please share any recommended reading ahead of the lecture.

• Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009 Jan 29;360(5):470-80.
• Loss of B Cells in Patients with Heterozygous Mutations in IKAROS. N Engl J Med. 2016 Mar 17;374(11):1032-1043
• Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer Cell. 2018 May 14;33(5):937-948
• Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J Clin Invest. 2018 Jul 2;128(7):3071-3087