Analysis of the T cell repertoire in cancer patients: unveiling the antitumor immune response in humans

• Grant number: 14/25988-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2015
• End date: May 31, 2019
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Jose Alexandre Marzagão Barbuto
• Grantee: Mariana Pereira Pinho
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 16/01137-8 - Analysis of the tumor-antigen specific T cell repertoire in healthy donors using T cell libraries, BE.EP.DR

Abstract

Tumorigenesis is accompanied by the accumulation of mutations and aberrant expression of various proteins by the transformed cells, which are recognized as tumor-associated antigens (TAAs) by the adaptive immune response. However, high affinity T cells that would recognize TAAs, supposedly, should have been eliminated by the central tolerance, as these antigens are very similar or even identical to self-antigens. Nevertheless, it is possible to detect tumor antigen-specific T cells in cancer patients, but little can be said about the complete repertoire of tumor-reactive lymphocytes (since, usually, this kind of analysis is performed by evaluating the presence of T lymphocytes capable of recognizing one specific epitope of one TAA). On the other hand, the adaptive immune response is, sometimes, able to specifically recognize and eliminate tumor cells, a characteristic that has been exploited in the development of immunotherapeutic protocols. Yet, a better understanding of how the immune system recognizes and responds in vivo to TAAs, at an individual cell level, would provide a formidable tool to achieve better clinical results in cancer immunotherapy. Therefore, this project aims to develop an in depth study of the TAAs-specific T lymphocyte repertoire in cancer patients, determining the frequency, affinity and response pattern of these T cells, at various stages of disease progression and therapy. For this, the TAA-specific T lymphocyte repertoire will be assessed by using MHC multimers and by screening T cell libraries of healthy donors and cancer patients. These libraries will be constructed by expansion of all T cell clones present in blood samples collected at various moments, separated according to their surface phenotype into known T cell subpopulations (naïve/central memory/effector memory or Th1/Th2/Th17/Th22) and challenged with specific antigens or tumor lysates. An attempt to evaluate Treg responses, by using, as readout, the calcium influx induced by contact with TAA-loaded antigen-presenting cells, will also be made. We anticipate that unveiling the TAA-specific repertoire in different stages of disease will establish new parameters to evaluate and interfere in the relationship between the immune system and cancers, thus, hopefully providing Medicine with improved ways to treat these diseases. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PINHO, MARIANA PEREIRA; PATENTE, THIAGO ANDRADE; FLATOW, ELIZABETH ALEXANDRA; SALLUSTO, FEDERICA; MARZAGAO BARBUTO, JOSE ALEXANDRE. Frequency determination of breast tumor-reactive CD4 and CD8 T cells in humans: unveiling the antitumor immune response. ONCOIMMUNOLOGY, v. 8, n. 8, MAY 2019. (14/25988-1, 16/01137-8)

PINHO, MARIANA P.; LEPSKI, GUILHERME A.; REHDER, ROBERTA; CHAUCA-TORRES, NADIA E.; EVANGELISTA, GABRIELA C. M.; TEIXEIRA, SARAH F.; FLATOW, ELIZABETH A.; DE OLIVEIRA, JAQUELINE V.; FOGOLIN, CARLA S.; PERES, NATALY; et al. Near-Complete Remission of Glioblastoma in a Patient Treated with an Allogenic Dendritic Cell-Based Vaccine: The Role of Tumor-Specific CD4+T-Cell Cytokine Secretion Pattern in Predicting Response and Recurrence. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 10, p. 10-pg., 2022-05-01. (14/25988-1, 16/01137-8)

PINHO, M. P.; BARBUTO, J. M.. Breast cancer patients have multifunctional tumor-reactive CD4 T cells in both blood and tumor. EUROPEAN JOURNAL OF CANCER, v. 110, p. 1-pg., 2019-03-01. (14/25988-1)

PATENTE, THIAGO A.; PINHO, MARIANA P.; OLIVEIRA, ALINE A.; EVANGELISTA, GABRIELA C. M.; BERGAMI-SANTOS, PATRICIA C.; BARBUTO, JOSE A. M.. Human Dendritic Cells: Their Heterogeneity and Clinical Application Potential in Cancer Immunotherapy. FRONTIERS IN IMMUNOLOGY, v. 9, JAN 21 2019. (14/25988-1, 16/01137-8, 14/26437-9)

PINHO, MARIANA PEREIRA; MARZAGAO BARBUTO, JOSE ALEXANDRE. Commentary: Soluble CD83 Alleviates Experimental Autoimmune Uveitis by Inhibiting Filamentous Actin-Dependent Calcium Release in Dendritic Cells. FRONTIERS IN IMMUNOLOGY, v. 9, p. 2-pg., 2018-11-15. (14/25988-1)

PINHO, MARIANA P.; PATENTE, THIAGO A.; FLATOW, ELIZABETH A.; BARBUTO, JOSE ALEXANDRE M.. Frequency of tumor-reactive T cells in the blood of breast cancer patients and healthy donors.. CANCER IMMUNOLOGY RESEARCH, v. 8, n. 4, p. 1-pg., 2020-04-01. (14/25988-1)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

PINHO, Mariana Pereira. Analysis of the T cell repertoire in cancer patients: unveiling the antitumor immune response in humans. 2019. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.