Dissecting the crossroads of circulating and tissue-resident T cells in solid tumors

Alvaro Lladser (Fundacion Ciencia & Vida, Universidad San Sebastián)

11 septembre 2025

Séminaire
Alvaro Lladser

Infos pratiques

12:00 - 13:00
Salle Rosalind Franklin
Professionnel de recherche
Accès mobilité réduite

Clear cell renal cell carcinoma (ccRCC) is a prevalent and aggressive subtype of kidney cancer. Immunotherapies that boost the ability of CD8+ T cells to eliminate cancer cells have become a standard of care for ccRCC. However, tumor infiltration of CD8+ T cells can result in contradicting clinical outcomes, potentially due to the functional heterogeneity among tumor-specific CD8+ T cells. In this study, we observed that ccRCC tumors are infiltrated by circulating (Tcirc) and tissue-resident (Trm) memory CD8+ T cells that specifically recognize autologous RCC cells in an HLA class I-dependent manner. Trm cells exhibited higher tumor reactivity but reduced stemness potential and a more exhausted state, whereas Tcirc cells retained higher stemness and cytotoxic potential. Single-cell transcriptomics revealed a rather heterogenous composition of memory populations, including cytotoxic and progenitor Tcirc subsets, as well as multiple Trm subsets, including exhausted Trm cells. TCR and trajectory analyses indicate that circulating progenitors lose their circulation, cytotoxicity and stemness potential within the tumor microenvironment while progressively acquiring a tissue-resident differentiation program followed by a terminal differentiation state. Interestingly, tumor enrichment of Trm and cytotoxic Tcirc cells predicts better survival, while exhausted Trm and total CD8+ T cells predict worse survival in RCC patients. Our findings provide new insights into the differentiation pathways and clinical impact of tumor-specific memory CD8+ T cells infiltrating human RCC tumors.

Adoptive T cell therapy (ACT) has demonstrated remarkable efficacy in treating hematological cancers. However, its efficacy against solid tumors remains limited and the emergence of cancer cells that lose expression of targeted antigens promotes resistance to ACT. The mechanisms underlying effective and durable ACT-mediated tumor control are incompletely understood. Here, we show that adoptive transfer of TCR-transgenic CD8+ T cells that efficiently eliminates established murine tumors induces tumor accumulation of CD8+ T cells exhibiting tumor-reactive phenotypes. Interestingly, host CD8+ T cells contributed to ACT-mediated elimination of primary tumors and rejected ACT-resistant melanoma cells lacking the targeted antigen. Mechanistically, ACT induced TNF-α- and dendritic cell-dependent tumor accumulation of endogenous CD8+ T cells and effective tumor elimination. Importantly, although lymphodepleting preconditioning enhanced expansion of transferred cells and ACT-mediated tumor elimination, it impaired host antitumor immunity and abrogated protection against ACT-resistant tumors. Tumor enrichment of transcriptional signatures associated with TNF-α signaling, cross-presenting dendritic cells and tumor-specific CD8+ T cells in correlated with favorable responses to ACT and increased survival in human cancers. Our findings reveal that long-term efficacy of ACT is determined by the interplay between transferred and endogenous CD8+ T cells and is undermined by lymphodepleting preconditioning, which ultimately favors ACT resistance.