Boosting antitumor activity of NK cells from triple-negative breast cancer patients through epigenetic modulation

• Grant number: 24/13774-9
• Support Opportunities: Scholarships in Brazil - Master
• Start date: December 01, 2024
• End date: April 14, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Vladmir Cláudio Cordeiro de Lima
• Grantee: Daniela Delechiave
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated research grant: 18/14034-8 - Characterization of chromatin and transcriptional landscapes of T cells from gastric adenocarcinoma patients as a tool to discover immunotherapy targets, AP.JP

Abstract

As the tumor evolves, an immunosuppressive tumor microenvironment (TME) emerges and, as a result, immune cells become dysfunctional and lose the ability to eliminate tumor cells. In this sense, NK cells lose their ability to produce cytotoxic granules and thus become incapable of effectively destroying tumor cells. Immune checkpoint inhibitors (ICI), such as anti-PD1 and anti-CTLA-4, can be used as therapy approach for cancer patients, as they reinvigorate immune cells and restore their tumor-eliminating ability. Since the available ICIs are not totally effective in reinvigorating terminally exhausted cells, here we will explore therapeutic combinations aiming at improving the ICI response on NK cells. Given the epigenetic remodeling found in terminally exhausted immune cells, we propose that reversing this process in immune cells through epigenetic therapies may be essential to rescuing their anti-tumor functions, which could emerge as a therapeutic alternative for patients that are refractory to immunotherapy. Our preliminary data show that epigenetic therapy is effective in modulating the effector phenotype of tumor-infiltrating lymphocytes (TILs) of patients with clear cell renal cell carcinoma, suggesting that other tumor-infiltrating immune cell populations in different tumor types might also be epigenetically reprogrammable. By suppressing the CBP/p300 complex, we aim to restore the anti-tumor abilities of tumor-infiltrating NK (TI-NK) cells of patients with triple-negative breast cancer (TNBC). In a pilot study led by the student Daniela Delechiave, our epigenetic approach was able to boost the expression of cytotoxic and inflammatory mediators in circulating NK cells, suggesting a possible epigenetic control on the function of TI-NK cells in TNBC. In summary, restoring the anti-tumor abilities of terminally exhausted TI-NK cells through epigenetic remodeling may aid in the development of promising combinatorial therapies for TNBC patients refractory to immunotherapy. (AU)