Arantxa Agesta, Chloé Ferrand, Anne-Louise Le Dorze, Cindy Peillex, Nadège Carrié, Rébecca Barascud, Arthur Palak, Lucie Esteban, Tanguy Bernal, Emeline Joulia, Céline Colacios, Tania Margarido Pereira, Romain Peroceschi, Andrea Pichler, Adeline Chaubet, Margot Zahm, Abdelhadi Saoudi, Hicham El Costa, Véronique Adoue, Benjamin Y. Lu, Liliana E. Lucca, Ludovic Martinet, Anne S. Dejean
T helper (Th) cells contribute to tumor immunity, yet the subsets and differentiation programs involved remain unclear. Here, we show that the transcription factor Eomesodermin (Eomes) is essential for Th-mediated anti-tumor immunity. Eomes orchestrated the differentiation and maintenance of an exhausted-like Th cell lineage, transcriptionally and functionally distinct from conventional effector or memory Th subsets. This Eomes-dependent program was enhanced by 4-1BB stimulation and promoted effective Th-cell-mediated tumor control. The progenitor subset of this lineage (pTh) expressed stemness-associated transcription factors, displayed self-renewal capacity, and seeded effector subsets capable of controlling tumor growth. At the transcriptional level, Eomes supported the survival, metabolic fitness, and apoptotic resistance of this lineage. Eomes⁺ pTh cells exhibited conserved transcriptional features in humans across multiple tumor types. As the most expanded Th cell population upon immune checkpoint inhibitor therapy, targeting these cells has potential to improve current immunotherapies.