Thesis Defense: Sarah KUNZ « Ciblage de SLC3A2 dans les adénocarcinomes pulmonaires »

Thesis directors: Dr Chloé FERAL (IRCAN) & Dr. Christophe HENRY (Sanofi)

Please note that a short confidentiality form will need to be signed before the defense.

Abstract: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally and in France, largely due to late-stage diagnosis and the ineffectiveness of conventional treatments. Although immunotherapies targeting the PD-1/PD-L1 axis have significantly improved survival in certain patients, they benefit only a minority due to innate and adaptive resistance mechanisms. The extracellular matrix (ECM) plays a critical role in this resistance by forming a physical barrier that limits T lymphocyte infiltration and reduces the efficacy of PD-1/PD-L1 blockade. A strategy targeting the ECM therefore represents a major therapeutic opportunity to potentiate existing immunotherapies. SLC3A2 is a type II transmembrane glycoprotein exerting two central functions: it constitutes the heavy chain of the CD98 complex, regulating the membrane trafficking of the catalytic chain, and interacts with integrins,ECM receptors, to regulate collagen assembly and matrix stiffness. Through this latter role, SLC3A2 amplifies integrin-dependent signaling, modulating mechanotransduction, the cellular capacity to convert mechanical signals into biochemical responses. SLC3A2 expression is increased in numerous carcinomas and correlates with poor prognosis. This protein is involved in proliferation, migration, matrix remodeling, and ferroptosis. At the pulmonary level, SLC3A2 constitutes an early tumor marker and promotes pro-tumoral macrophage polarization, creating a permissive microenvironment. These multiple functions establish SLC3A2 as an ideal therapeutic target. Recent studies in murine models using either genetic deletion or a novel antibody targeting SLC3A2 demonstrate significant therapeutic benefit. The goal of my PhD studies was to generate and analyse novel tools targeting SLC3A2.