Characterization of chromatin and transcriptional landscapes of T cells from gastric adenocarcinoma patients as a tool to discover immunotherapy targets

• Grant number: 18/14034-8
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: April 01, 2020
• End date: March 31, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Tiago da Silva Medina
• Grantee: Tiago da Silva Medina
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated researchers: Cheryl Arrowsmith ; Daniel Diniz de Carvalho ; Diana Noronha Nunes ; Fabio Albuquerque Marchi ; Israel Tojal da Silva ; Kenneth John Gollob ; Vladmir Cláudio Cordeiro de Lima
• Associated scholarship(s): 24/13774-9 - Boosting antitumor activity of NK cells from triple-negative breast cancer patients through epigenetic modulation, BP.MS; 24/01953-6 - Characterisation of the spatial organisation and functions of tumour-infiltrating immune cells in endometrial cancer patients as a strategy for discovering immunotherapy targets, BP.DR; 24/01951-3 - CBP/p300 as a target for boosting CAR-T cell response: implications in haematological malignancies and solid tumours, BP.DR; + associated scholarships 24/01907-4 - Evaluation of the Therapeutic Potential of Germinal Center B Cells in Clear Cell Renal Cell Carcinoma Patients, BP.PD; 22/00747-8 - Evaluation of the antitumoral activity of CD39+ T cells in patients with clear cell renal cell carcinoma, BP.DR; 20/10299-7 - PIWIL4 as a central regulator of endogenous retroviral elements in Gastric Cancer: implications for immunopathogenesis and immunotherapy?, BP.PD; 21/00643-5 - Characterization of chromatin and transcriptional landscapes of T cells from diffuse-type gastric adenocarcinoma patients as a tool to discover immunotherapy targets, BP.MS - associated scholarships

Abstract

The immune system in cancer patients is normally compromised, as the tumor microenvironment has a drastic effect on immune cell populations, given its ability to promote alternatively activated immune cells. Such immune cells are unable to destroy cancer (initiating) cells, as they are either exhausted or polarized towards an anti-inflammatory profile. Immune checkpoint inhibitors have emerged as a promising strategy to enhance cancer immunotherapy. Anti-PD-1 is of particular interest, as clinical trials have shown its tremendous impact on the immune response due to its capacity of potentiating CD8 T cell functionality. However, the effect of anti-PD-1 treatment on other immune cell populations is largely unknown. Here, we will extensively characterize exhausted CD8 and CD4 T cells, isolated from tissue resections of gastric adenocarcinoma patients, using epigenetic and single cell transcriptomic tolls, as reliable data can be generated with a limited number of cells. This will allow us to discover promising molecular candidates involved in the induction and maintenance of exhausted immune cells within the tumor microenvironment of gastric adenocarcinoma patients. We will further investigate whether these molecular candidates also contribute to the outcome of gastric cancer in functional in vitro immunoassays. Therefore, we will evaluate whether the in vitro inhibition of a particular candidate in combination with anti-PD-1 treatment will improve the antitumoral response of CD8 and CD4 T cells. More importantly, we will assess whether CD19-HLA-DR+ immune cell populations (likely to be plasma cells) act as long-lived antigen presenting cells to sustain a pool of T cells within the gastric tumor microenvironment. We expect to find candidates that, alone or in combination with anti-PD-1 immunotherapy, shape immune cell populations towards a pro-inflammatory profile and consequently facilitate tumor elimination, which will open perspectives for cancer treatment. (AU)

Scientific publications

(4)

(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)

KINKER, GABRIELA SARTI; VITIELLO, GLAUCO AKELINGHTON FREIRE; FERREIRA, WALLAX AUGUSTO SILVA; CHAVES, ALEXANDRE SILVA; CORDEIRO DE LIMA, VLADMIR CLAUDIO; MEDINA, TIAGO DA SILVA. B Cell Orchestration of Anti-tumor Immune Responses: A Matter of Cell Localization and Communication. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 9, JUN 7 2021. (18/14034-8, 19/25129-2, 14/50943-1)

VITIELLO, GLAUCO AKELINGHTON FREIRE; FERREIRA, WALLAX AUGUSTO SILVA; CORDEIRO DE LIMA, VLADMIR CLAUDIO; MEDINA, TIAGO DA SILVA. Antiviral Responses in Cancer: Boosting Antitumor Immunity Through Activation of Interferon Pathway in the Tumor Microenvironment. FRONTIERS IN IMMUNOLOGY, v. 12, DEC 2 2021. (20/10299-7, 14/50943-1, 18/14034-8)

LIMA, G. C.; CHURA-CHAMBI, R. M.; MORGANTI, L.; SILVA, V. J.; CABRAL-PICCIN, M. P.; ROCHA, V.; MEDINA, T. S.; RAMOS, R. N.; LUZ, D.. Recombinant human TIM-3 ectodomain expressed in bacteria and recovered from inclusion bodies as a stable and active molecule. FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY, v. 11, p. 11-pg., 2023-07-31. (22/04560-0, 18/14034-8, 21/04307-0)

DE CAMPOS, NAJLA SANTOS PACHECO; DE OLIVEIRA BESERRA, ADRIANO; PEREIRA, PEDRO HENRIQUE BARBOSA; CHAVES, ALEXANDRE SILVA; FONSECA, FERNANDO LUIZ AFFONSO; DA SILVA MEDINA, TIAGO; DOS SANTOS, TIAGO GOSS; WANG, YUFEI; MARASCO, WAYNE ANTHONY; SUAREZ, ELOAH RABELLO. Immune Checkpoint Blockade via PD-L1 Potentiates More CD28-Based than 4-1BB-Based Anti-Carbonic Anhydrase IX Chimeric Antigen Receptor T Cells. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 10, p. 17-pg., 2022-05-01. (14/50943-1, 18/14034-8, 18/17656-0, 18/25541-8)