000151126 001__ 151126
000151126 005__ 20250227101503.0
000151126 0247_ $$2doi$$a10.1136/jitc-2021-003351
000151126 0248_ $$2sideral$$a125758
000151126 037__ $$aART-2021-125758
000151126 041__ $$aeng
000151126 100__ $$aConde E.
000151126 245__ $$aEpitope spreading driven by the joint action of CART cells and pharmacological STING stimulation counteracts tumor escape via antigen-loss variants
000151126 260__ $$c2021
000151126 5060_ $$aAccess copy available to the general public$$fUnrestricted
000151126 5203_ $$aBackground 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. In this setting, the CART/STING-L combination, but not the monotherapy with CART cells or STING-L, restrained tumor progression and enhanced overall survival, showing abscopal effects on distal STING-L-non-treated tumors. Interestingly, a secondary immune response against non-chimeric antigen receptor-targeted Ags (epitope spreading), as determined by major histocompatibility complex-I-tetramer staining, was fostered and its intensity correlated with the efficacy of the combination. This was consistent with the oligoclonal expansion of host T cells, as revealed by in-depth T-cell receptor repertoire analysis. Moreover, only in the combination group did the activation of endogenous T cells translate into a systemic antitumor response. Importantly, the epitope spreading and the antitumor effects of the combination were fully dependent on host STING signaling and Batf3-dependent DCs, and were partially dependent on Perf release by CART cells. Interestingly, the efficacy of the CART/STING-L treatment also depended on STING signaling in CART cells. Conclusions Our data show that 2'3'-cGAMP is a suitable adjuvant to combine with CART-cell therapy, allowing the induction of an endogenous T-cell response that prevents the outgrowth of Ag-loss tumor variants.
000151126 536__ $$9info:eu-repo/grantAgreement/ES/AEI/PID2020-113963RB-I00$$9info:eu-repo/grantAgreement/ES/DGA-FEDER/B29-17R$$9info:eu-repo/grantAgreement/ES/MCIU-AEI/SAF2017-83120-C2-1-R
000151126 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000151126 590__ $$a12.485$$b2021
000151126 591__ $$aONCOLOGY$$b25 / 245 = 0.102$$c2021$$dQ1$$eT1
000151126 591__ $$aIMMUNOLOGY$$b18 / 162 = 0.111$$c2021$$dQ1$$eT1
000151126 592__ $$a3.45$$b2021
000151126 593__ $$aCancer Research$$c2021$$dQ1
000151126 593__ $$aImmunology$$c2021$$dQ1
000151126 593__ $$aPharmacology$$c2021$$dQ1
000151126 593__ $$aOncology$$c2021$$dQ1
000151126 593__ $$aMolecular Medicine$$c2021$$dQ1
000151126 594__ $$a14.3$$b2021
000151126 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000151126 700__ $$aVercher E.
000151126 700__ $$aSoria-Castellano M.
000151126 700__ $$aSuarez-Olmos J.
000151126 700__ $$aMancheno U.
000151126 700__ $$aElizalde E.
000151126 700__ $$aRodriguez M.L.
000151126 700__ $$aGlez-Vaz J.
000151126 700__ $$aCasares N.
000151126 700__ $$aRodriguez-Garcia E.
000151126 700__ $$aHommel M.
000151126 700__ $$aGonzalez-Aseguinolaza G.
000151126 700__ $$aUranga-Murillo I.
000151126 700__ $$0(orcid)0000-0003-0154-0730$$aPardo J.$$uUniversidad de Zaragoza
000151126 700__ $$aAlkorta G.
000151126 700__ $$aMelero I.
000151126 700__ $$aLasarte J.
000151126 700__ $$aHervas-Stubbs S.
000151126 7102_ $$11011$$2566$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Inmunología
000151126 773__ $$g9, 11 (2021), [16 pp.]$$pJ. immunotherap. cancer$$tJournal for immunotherapy of cancer$$x2051-1426
000151126 8564_ $$s9362370$$uhttps://zaguan.unizar.es/record/151126/files/texto_completo.pdf$$yVersión publicada
000151126 8564_ $$s3351159$$uhttps://zaguan.unizar.es/record/151126/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000151126 909CO $$ooai:zaguan.unizar.es:151126$$particulos$$pdriver
000151126 951__ $$a2025-02-27-09:25:41
000151126 980__ $$aARTICLE