LTβR 激动通过调节肿瘤微环境促进抗肿瘤免疫应答

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 in many cancer types. Elucidation of the molecular mechanisms underlying intratumoral HEV and TLS formation and their contribution to antitumor responses may facilitate the development of improved treatment strategies. Lymphotoxin receptor (LT R) signaling is a critical regulator of lymph node organogenesis and can cooperate with antiangiogenic and immune checkpoint blockade treatment to augment tumor-associated HEV formation. In this study, we demonstrated that LT R signaling modulates the tumor microenvironment via multiple mechanisms to promote antitumor T-cell responses. Systemic activation of the LT R 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 LT R agonism on DC activation and maturation and associated DC-mediated T-cell activation. Single-agent LT R agonist treatment inhibited syngeneic tumor growth in a CD8+ T-cell-dependent and HEV-dependent manner, and the LT R agonist enhanced antitumor effects of anti-PD-1 and CAR T-cell therapies. An in vivo tumor screen for TLS-inducing cytokines revealed that the combination of LT R agonism and lymphotoxin expression promoted robust intratumoral TLS induction and enhanced tumor responses to anti-CTLA4 treatment.

Collectively, this study highlights crucial functions of LT R signaling in modulating the tumor microenvironment and could inform future HEV/TLS-based strategies for cancer treatments. Significance: LT R mediates tumor-specific high endothelial venule formation and immunomodulation of the tumor microenvironment that promotes antitumor immune responses, supporting LT R agonism as an approach to enhance the antitumor efficacy of immunotherapies.