| Autor: |
An D; Regeneron (United States), Tarrytown, NY, United States., Chen G; Regeneron (United States), Tarrytown, NY, United States., Cheng WY; Regeneron (United States), Tarrytown, NY, United States., Mohrs K; Regeneron (United States), Tarrytown, NY, United States., Adler C; Regeneron (United States), Tarrytown, NY, United States., Gupta NT; Regeneron (United States), Tarrytown, NY, United States., Atwal GS; Regeneron (United States), Tarrytown, NY, United States., DiLillo DJ; Regeneron (United States), Tarrytown, NY, United States., Daly C; Regeneron, Tarrytown, NY, United States., Lin JC; Regeneron (United States), Tarrytown, NY, United States., Kuhnert F; Regeneron (United States), Tarrytown, NY, United States. |
| Abstrakt: |
The presence of high endothelial venules (HEV) and tertiary lymphoid structures (TLS) in solid tumors is correlated with favorable prognosis and better responses to immune-checkpoint blockade (ICB) in many cancer types. Elucidation of the molecular mechanisms underlying intratumoral HEV and TLS formation and their contribution to anti-tumor responses may facilitate development of improved treatment strategies. Lymphotoxin beta receptor (LTβR) signaling is a critical regulator of lymph node organogenesis and can cooperate with antiangiogenic and ICB treatment to augment tumor-associated HEV formation. Here, we demonstrated that LTβR signaling modulates the tumor microenvironment via multiple mechanisms to promote anti-tumor T cell responses. Systemic activation of the LTβR pathway via agonistic antibody treatment induced tumor-specific HEV formation, upregulated the expression of TLS-related chemokines, and enhanced dendritic cell (DC) and T cell infiltration and activation in syngeneic tumor models. In vitro studies confirmed direct effects of LTβR agonism on DC activation and maturation and associated DC-mediated T cell activation. Single agent LTβR agonist treatment inhibited syngeneic tumor growth in a CD8+ T cell- and HEV-dependent manner, and the LTβR agonist enhanced anti-tumor effects of anti-PD-1 and CAR T cell therapies. An in vivo tumor screen for TLS-inducing cytokines revealed that the combination of LTβR agonism and lymphotoxin alpha (LT⍺) expression promoted robust intratumoral TLS induction and enhanced tumor responses to anti-CTLA-4 treatment. Collectively, this study highlights crucial functions of LTβR signaling in modulating the tumor microenvironment and could inform future HEV/TLS-based strategies for cancer treatments. |
