Epitope spreading driven by the joint action of CART cells and pharmacological STING stimulation counteracts tumor escape via antigen-loss variants

Background Target antigen (Ag) loss has emerged as a major cause of relapse after chimeric antigen receptor T (CART)-cell therapy. We reasoned that the combination of CART cells, with the consequent tumor debulking and release of Ags, together with an immunomodulatory agent, such as the stimulator o...

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Detalles Bibliográficos
Autores: Vercher-Herráez, E. (Enric)|||/items/e498ac44-4d07-4ffb-b4fc-946f022d40cf, Soria-Castellano, M. (Marta)|||/items/c92447ae-45fa-4b64-9a2e-4a8ee16fe07f, Suarez-Olmos, J. (Jesús)|||/items/bed0ebff-ce13-4c8a-aa5e-31c8093b3205, Mancheño, U. (Uxua)|||/items/7e9b5aee-3e45-40fb-b87f-19be6c19dd6c, Elizalde, E. (Edurne)|||/items/03f9b244-8b6f-4020-8fe2-a16225f7116d, Rodríguez, M.L. (M. Luis)|||/items/3e1599fe-578c-4452-8603-07995fe3a731, González-Vaz, J. (Javier)|||/items/9d321bb0-f713-4608-8d35-15b1c9588b76, Casares-Lagar, N. (Noelia)|||/items/32524a9b-f393-47ee-bf77-0737c65e0b7b, Rodríguez-García, E. (Estefanía)|||/items/c409e10b-5cd7-4095-95f2-2c321e5293c3, Hommel, M. (Mirja)|||/items/a467e5e2-d341-40b9-b79a-020585a49522, González-Aseguinolaza, G. (Gloria)|||/items/cb28732d-02bf-4339-ab60-ff738ee191ac, Uranga-Murillo, I. (Iratxe)|||/items/a6ea79e7-c31f-4858-a49d-bd9a52503b99, Pardo, J. (Julián)|||/items/76e8f690-a6b1-4f38-99d3-eb1c37dbeaae, Alkorta-Aranburu, G. (Gorka)|||/items/1b68902d-4b46-4598-959f-c3dfe99df2c8, Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e, Lasarte-Sagastibelza, J.J. (Juan José)|||/items/e366ad83-3db4-41ec-a9da-ed9159ba5c0c, Hervas-Stubbs, S. (Sandra)|||/items/8f56cb52-4465-4428-8acf-e50439c6be8f, Conde-Gallastegi, E. (Enrique)|||/items/6fe61463-13fd-4163-a854-6a1d1d15a934
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/62856
Acceso en línea:https://hdl.handle.net/10171/62856
Access Level:acceso abierto
Palabra clave:Adaptive immunity
Combined modality therapy
Immunotherapy
Adoptive
Receptors
Chimeric antigen
Tumor escape
Descripción
Sumario:Background Target antigen (Ag) loss has emerged as a major cause of relapse after chimeric antigen receptor T (CART)-cell therapy. We reasoned that the combination of CART cells, with the consequent tumor debulking and release of Ags, together with an immunomodulatory agent, such as the stimulator of interferon gene ligand (STING-L) 2 ' 3 '-cyclic GMP-AMP (2 ' 3 '-cGAMP), may facilitate the activation of an endogenous response to secondary tumor Ags able to counteract this tumor escape mechanism. Methods Mice bearing B16-derived tumors expressing prostate-specific membrane Ag or gp75 were treated systemically with cognate CART cells followed by intratumoral injections of 2 ' 3 '-cGAMP. We studied the target Ag inmunoediting by CART cells and the effect of the CART/STING-L combination on the control of STING-L-treated and STING-L-non-treated tumors and on the endogenous antitumor T-cell response. The role of Batf3-dependent dendritic cells (DCs), stimulator of interferon gene (STING) signaling and perforin (Perf)-mediated killing in the efficacy of the combination were analyzed. Results Using an immune-competent solid tumor model, we showed that CART cells led to the emergence of tumor cells that lose the target Ag, recreating the cancer immunoediting effect of CART-cell therapy.

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