Diana Torres, Immunology Department, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City­‐04510, Mexico.

Tel: (+5552) 562 231 53; Email: dianatg@comunidad.unam.mx

 

I was awarded with an International Scholarship from the Gender Equality and Career Development Committee (GEC) of the International Union of Immunology Societies (IUIS) to attend to the first international IUIS­‐ALAI­‐SMI Oncoimmunology­‐Mexico course, which was held from 5­‐8 October 2016 at the Misión Hotel, San Miguel de Allende, Guanajuato, México. This course was organized by the International Union of Immunological Societies (IUIS), the Asociación Latinoamericana de Inmunología (ALAI), and the Sociedad Mexicana de Inmunología (SMI). The session chairs were Dr. Rosana Pelayo (Treasurer of the SMI), and Dr. Leopoldo Santos (President of the ALAI).

The main aim of this course was to improve, share and update our knowledge in the oncoimmunology field. This course was designed to interact with oncoimmunologists and physicians, who are experts in epidemiology, etiology of the cancer, oncogenesis, tumor immunology, inflammatory microenvironment, cancer immunotherapy, among other specialties. This interaction was prompted through lectures and discussion sessions carried out between students, young researchers, and the speakers.

The course was introduced by Dr. Michelle Letarte (Chair of the IUIS Education Committee), and Dr. Leopoldo Santos, who presented the guidelines and the aim of the course.

During this course, the following lectures and activities were carried out:

DAY 1

1. Hallmarks of Cancer and Epidemiology: Dr. Marcos Gutiérrez (IMSS, MX)
2. How Cancer Cells Interact with Immune System: Dr. José Moreno (HJM, MX)
3. Effector  Cell  Populations  of  Anti­‐Tumor  Immunity  focus  on  T  cells:  Dr.  Vianney  Ortiz (CINVESTAV, MX)
4. Inhibitory Mechanisms in Cancer: Dr. Dario Vignali (U. Pittsburgh, USA)
5. Cancer Stem Cells: Dr. Mónica Guzmán (Weill Cornell Medical College, NY, USA)

Through these lectures we reviewed the epidemiology, etiology of cancer and the main hallmarks of cancer. We examined some examples of immune response in cancer, immunological surveillance, mechanisms of adaptive immune response in cancer, the tumor microenvironment; we also reviewed the theory of the 3Es of cancer. We analyzed the advantages and disadvantages of some immune checkpoint receptors used as cancer immunotherapy (like anti­‐PD­‐L1, anti­‐PD­‐1, anti­‐CTLA­‐ 4, anti­‐LAG3, anti­‐TIM3, among others). Also, we discussed the significance of regulatory T cells (Treg) in  human  cancer;  and  the  Sema4a­‐  Nrp­‐1  pathway  associated  with  the  cell  stability  of  Treg. Moreover, the definition and features of the cancer stem cells (CSC) were reviewed, as well as the two models of CSC growth (the Hierarchical model, and the Stochastic model). Finally, we studied the chimeric antigen receptor (CAR) T cell therapy.

DAY 2

1. Tumor Microenvironment: Hematological Malignancies as a Paradigm of Study: Dr. Eugenia Flores­‐Figueroa (IMSS, MX)
2. Immune Regulation in Cancer: Dr. Thomas Gajewski (U. Chicago, USA)
3. Role of Endothelial Cells in Tumor Progression: Dr. Michelle Letarte (U. Toronto, CA)
4. Signaling Pathways in Cancer: Dr. Martha Robles (FM, UNAM, MX)
5. Poster Session
6. Vaccination in Cancer: Dr. Diego Croci (IBYME, ARG)
7. Solid Tumors: Dr. Flavio Salazar (IMI, CHL)
8. Pathogen and Cancer: Dr. Ezequiel Fuentes­‐Pananá (HIMFG, MX)

On this day we studied the stroma features of pancreatic cancer and Acute Myeloid Leukemia (AML). We discussed the clinical application and biological aspects of the immunoregulation by Mesenchymal Stem Cells (MSC).  On the other hand, the immunobiology of Tcell­‐inflamed and non­‐ inflamed infiltrated in the tumor microenvironment was discussed. Additionally, we reviewed some examples  of  immune  escape  inhibitory  pathways  (like  PD­‐L1­‐PD1,  IDO  (tryptophan  metabolism), Foxp3­‐Treg   (extrinsic   suppressor   cells),   and   T   cell   anergy   (intrinsic   dysfunction   from   poor costimulation)).

The role of endothelial cells in the tumor microenvironment was analyzed through the review of angiogenesis markers associated with the tumor; the use of CD105 as a tool of identification of microvascular density associated to the prognostic of cancer; the leukocyte­‐ endothelial interaction by  means  of  the  regulation  of  adhesion  molecules  (like  P­‐selectin,  E­‐selectin,  L­‐selectin,  ICAM­‐1, ICAM­‐2, VCAM­‐1, among others).

Later,  we  reviewed  some  of  the  most  important  signaling  pathways  in  cancer,  like  the  TGF­‐b pathway, which has been associated to tumor suppression and progression; the MAPK family receptors; as well as the regulation of stem cell renewal by the Wnt pathway, along with its canonical and noncanonical transduction pathways: the Cell­‐polarity migration activation of Dvl (dishevelled), and the Wnt/Ca2+ pathway; also, the DKK protein family: inhibitors of the Wnt pathway.

On the other hand, we discussed some examples of vaccines in cancer, like peptides targeting specific cancer antigens, and DNA­‐based anticancer vaccines.  Moreover, we reviewed some examples of immunotherapies against solid tumors.

Finally, we analyzed the contribution of pathogens (viruses, parasites, and bacteria) to oncogenesis, over the direct and indirect mechanisms of transformation of cells: expression of oncogenes, insertion mutation, chronic inflammation, immunosuppression, and chronic antigenic stimulation.

 

DAY 3

1. Acute Leukemia Phenotyping: Euroflow Plataform: Dr. Maria Ines Goldaracena (LA Clinical Diagnostic, BD Biosciences)
2. Data Acquisition in the BD FACSCanto II and Cell Analyses in Infinicyt Software: B­‐ALL, CLL, MM, PCD: Dr. Maria Ines Goldaracena (LA Clinical Diagnostic, BD Biosciences), and Q.F.B. Angelica Juárez (Application Specialist, BD Biosciences)
3. Data Acquisition and Cell Analyses in the BD FACSCanto II: Dr. Eduardo Vadillo (CINVESTAV, MX) and Q.F.B. Angelica Juárez (Application Specialist, BD Biosciences)
4. Poster Session
5. Epigenetics of Oncological Processes: Dr. Joseph A. Bellanti (U. Georgetown, USA)
6. Breast Cancer: Dr. Gregorio Quintero (HG, MX)

In these lectures, we analyzed the Acute Leukemia Phenotype through the Euroflow Plataform; and we evaluated the pattern­‐expression of surface markers in CSC, depending on the tissue and type of cancer. Moreover, we reviewed different solid tumors cancer cells acquired in the BD FACSCanto II and analyzed through marker of CSC, like CD47, and CD44, which have been associated with the migration capacity of metastatic cells, and changes in the extracellular matrix that influence cell growth, survival, and differentiation.

Then, we studied the epigenetic regulation in cancer, through the review of some epigenetic mechanisms. Further, we examined the correlation between necrotic DNA and methylation, apoptotic DNA and hypomethylation, unmethylated DNA and oncogene activation, methylated DNA and tumor suppressor genes activation.

Lastly, we reviewed breast cancer epidemiology data, the TNM classification system, the types of breast cancer based on the receptor expression (ER, PR, HER2), the evolution and types of tumor­‐ removal surgeries in Mexico, the role of the BRCA1, BRCA2 mutations in the prognosis of patients, and general approaches for the treatment of breast cancer in Mexico.

DAY 4

1. Currently Available Anti­‐Cancer Immunotherapies: Dr. Lorenzo Galluzzi (INSERM, FR)
2. Autophagy and other Mechanisms of Neoplastic Cell Control: Dr. Lorenzo Galluzzi (INSERM, FR)
3. Immunological Effects of Chemotherapy and Targeted Anticancer Agents: Dr. Aitziber Buqué (INSERM, FR)
4. Precision Cancer Medicine and Neoantigens Discovery: Dr. Duane Hassane (Weill Cornell Medical College, NY, USA)
5. Concluding remarks: Dr. Michelle Letarte (U. Toronto, CA), Dr. Leopoldo Santos (CINVESTAV, MX), and Dr. Rosana Pelayo (IMSS, MX)

In this last session, we did a brief review of the main types of cancer immunotherapies: immunogenic cell death inducers, immunomodulatory mAbs, anticancer vaccines, oncolytic virotherapy, PRR agonists,   Macrophage­‐reprogramming   agents,   inhibitors   of   immunosuppressive   metabolism, immunostimulatory cytokines, adaptive cell transfer, tumor­‐targeting mAbs.

We analyzed the advantages and limitations of checkpoints blockers, immunostimulatory mAbs, CARs,  oncolytic  virotherapy,  DC­‐based  interventions  (Tumor  cell  lysates,  tumor­‐derived  RNA, recombinant TAAS, TAA­‐derived peptides), peptide­‐ and DNA­‐based vaccines (short epitopes, short epitopes + helper peptide, synthetic long peptides), TLR agonist, recombinant cytokines (IL­‐2, IFN­‐b, GM­‐CSF, IL­‐7/IL­‐15), modulators of purinergic signals (CD39/CD73 inhibitors, A2A/A2B inhibitors), radiation therapy and ICD (Cyclophosphamide, Bortezomib, Doxorubicin, Mitoxantrone, Oxaliplatin, Photodynamic therapy (PDT), Radiation).

Moreover, we discussed the role of immunosuppression, therapeutic settings, tumor rejection antigens, the self/non­‐selftheory in the limited effectiveness of cancer immunotherapies.

On the other hand, the general regulation of stress responses was studied, through the difference between regulated cell death (RCD) and the accidental cell death. Later, we analyzed the characteristic features of a dead cell.

Additionally, we reviewed the immunological effects of chemotherapy and targeted anticancer agents. Further, we discussed how to increase immunogenicity (antigenicity, adjuvants), and how therapy  can  induce  immunostimulation  (on­‐target,  off­‐target  (Therapy  acts  on  the immune  cell population or in the microenvironment)). At last, we analyzed the use of sequencing methods, dbSNP, and ExAC to discover neoantigen that will allow us to personalized the cancer therapies.

Finally, I want to take the chance to point out that I am very grateful to have been awarded with an International Scholarship from the Gender Equality and Career Development Committee (GEC) of the International Union of Immunology Societies (IUIS), therefore I want to express my gratitude to Dr. Olivera Finn (Chair from IUIS Gender Equality Career Development Committee), Dr. Michelle Letarte (Chair from IUIS Education Committee), Dr. Rosana Pelayo (Treasurer of the SMI), and Dr. Leopoldo Santos (President of the ALAI) for providing me the opportunity to improve my knowledge, and giving me the chance to interact with experts on oncoimmunology, which allowed me to enrich my proficiency in this field.