Figueroa et al. demonstrated that lasting efficacy of adoptive T cell therapy (ACT) against solid tumors relied not only on the antitumor activity of transferred T cells, but also on their ability to expand host CD8+ T cells in a TNF- and cDC1-dependent manner. Host CD8+ T cells protected against rechallenge with ACT-resistant antigen-negative tumor cells. Lymphodepleting preconditioning promoted transferred T cell expansion, but impaired host immunity against antigen-loss variants. In patients with melanoma, enrichment of cDC1, TNF signaling, Tpex and Tex gene signatures correlated with clinical responses to ACT and better overall survival.
Contributed by Ute Burkhardt
ABSTRACT: Adoptive T cell therapy (ACT) is effective against hematologic cancers, but the mechanisms underlying durable responses in solid tumors remain unclear. We show that adoptively transferred CD8(+) T cells that eradicate established murine tumors promote expansion of host CD8(+) T cells exhibiting tumor-reactive and tissue-resident phenotypes that contribute to tumor elimination. Mechanistically, tumor necrosis factor (TNF) from transferred cells induces dendritic cell (DC)-dependent expansion of host CD8(+) T cells, conferring protection against ACT-resistant tumor cells lacking the targeted antigen. Lymphodepleting preconditioning promotes expansion of transferred cells and primary tumor eradication but impairs host antitumor immunity and abrogates protection against ACT-resistant tumors. In human tumors, increased TNF/DC/CD8(+) T cell profiles correlate with favorable ACT responses and improved survival. These findings reveal a TNF-dependent interplay between transferred and host CD8(+) T cells underlying durable antitumor immunity that is impaired by lymphodepleting preconditioning in mouse models, suggesting an underappreciated mechanism of ACT resistance.
Author Info: (1) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. (2) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. (3) Centro Basal Ciencia & V
Author Info: (1) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. (2) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. (3) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. Centro de Investigacin e Innovacin en Cncer, Fundacin Arturo Lpez Prez OECI Cancer Center, Santiago, Chile. (4) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. (5) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. Centro de Investigacin e Innovacin en Cncer, Fundacin Arturo Lpez Prez OECI Cancer Center, Santiago, Chile. (6) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. (7) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. (8) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. (9) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. (10) Laboratory of Immunology and Cellular Stress, Facultad de Medicina, Universidad de Chile, Santiago, Chile. (11) Laboratory of Immune Regulation, NDM Centre for Immuno-Oncology, University of Oxford, Oxford, UK. (12) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. Department of Anatomy, University of California San Francisco, San Francisco, CA, USA. (13) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. Centro de Biologa Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebastin, Santiago, Chile. (14) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. Laboratory of Immunology, Facultad de Ciencias, Universidad de Chile, Santiago, Chile. (15) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. Laboratory of Immunology and Cellular Stress, Facultad de Medicina, Universidad de Chile, Santiago, Chile. (16) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. vincenzo.borgna@uss.cl. Servicio de Urologa, Hospital Barros Luco Trudeau, Santiago, Chile. vincenzo.borgna@uss.cl. Facultad de Medicina, Universidad San Sebastin, Santiago, Chile. vincenzo.borgna@uss.cl. (17) Centro Basal Ciencia & Vida, Fundacin Ciencia & Vida, Santiago, Chile. alladser@cienciavida.org. Facultad de Medicina, Universidad San Sebastin, Santiago, Chile. alladser@cienciavida.org.
