Induction of tertiary lymphoid structures in tumor microenvironment to improve anti-tumoral immune checkpoint blockade efficacy

Roman Vion; Matthieu Roulleaux-Dugage; Ronan Flippot; Kaïssa Ouali; Mathieu Rouanne; Florian Clatot; MacLean Sellars; Stéphane Champiat; Nathalie Chaput; Christophe Massard; Francois-Xavier Danlos

doi:10.1016/j.ejca.2025.115572

Induction of tertiary lymphoid structures in tumor microenvironment to improve anti-tumoral immune checkpoint blockade efficacy

Eur J Cancer. 2025 Jun 9:225:115572. doi: 10.1016/j.ejca.2025.115572. Online ahead of print.

Affiliations

¹ Department of Medical Oncology, Henri Becquerel Institute, Rouen University, Rouen, France; INSERM U1245, IRON, Université de Rouen, Rouen, France.
² Drug Development Department, Gustave Roussy, Université Paris Saclay, Villejuif, France; Immunomonitoring laboratory, L.I.O, CNRS 3655 and INSERM US 23 AMMICA, Gustave Roussy, Université Paris Saclay, Villejuif, France.
³ Immunomonitoring laboratory, L.I.O, CNRS 3655 and INSERM US 23 AMMICA, Gustave Roussy, Université Paris Saclay, Villejuif, France; Department of Cancer Medicine, Gustave Roussy, Université Paris Saclay, Villejuif, France.
⁴ Drug Development Department, Gustave Roussy, Université Paris Saclay, Villejuif, France.
⁵ Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; INSERM U1015, CIC1428 BIOTHERIS, Gustave Roussy, Villejuif, France.
⁶ Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁷ Drug Development Department, Gustave Roussy, Université Paris Saclay, Villejuif, France; INSERM U1015, CIC1428 BIOTHERIS, Gustave Roussy, Villejuif, France.
⁸ Immunomonitoring laboratory, L.I.O, CNRS 3655 and INSERM US 23 AMMICA, Gustave Roussy, Université Paris Saclay, Villejuif, France.
⁹ Drug Development Department, Gustave Roussy, Université Paris Saclay, Villejuif, France; INSERM U1015, CIC1428 BIOTHERIS, Gustave Roussy, Villejuif, France; Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address: Francois-xavier.danlos@gustaveroussy.fr.

PMID: 40517527
DOI: 10.1016/j.ejca.2025.115572

Abstract

Immune checkpoint blockade (ICB) have revolutionized medical oncology, with the occurrence of cures in situations regarded as palliative. However, most patients develop resistance and the selection of responders remains difficult. The search for predictive biomarkers for immunotherapy has revealed that tertiary lymphoid structures (TLS) in the tumor microenvironment (TME) may be indicative of treatment effectiveness, since they may reflect the presence of an immune infiltrate with an anti-tumor effect. A better understanding of TLS neogenesis would help to establish anti-tumor strategies. For this purpose, this review outlines therapeutic modalities that could increase the immunogenicity and antigenicity of tumor cells, in particular immunogenic cell death (ICD), to turn "cold" tumors in "hot" tumors through interventions that promote the development of TLS. Second, the review describes the therapeutic strategies to enhance immune response against tumors, especially the resources to induce TLS, to strengthen cytotoxic T response / decrease Tregs and to promote the homing of immune cells. Future strategies should focus on a synergistic tactic combining both the enhancement of cancer cell immunogenicity and the stimulation of the immune system. PROVENANCE AND PEER REVIEW: Review commissioned by Aurelien Marabelle; externally peer reviewed.

Keywords: Immunology; Immunotherapy; Terrtiary lymphoid structure; Tumor micro environment.

Publication types

Review