Inhibition of integrin αvβ8-mediated TGFβ activation and active-TGFβ blockade promote anti-tumor immunity through distinct biological mechanisms

Transforming Growth Factor {beta} (TGF{beta}) is a potent immunosuppressor and a primary driver of resistance to cancer immunotherapy. While preclinical models have long suggested that TGF{beta} inhibition could synergize with immune checkpoint inhibitors, these effects have proven difficult to replicate in clinical settings. The highly regulated TGF{beta} pathway can be inhibited through various mechanisms, including neutralizing activated ligands or inhibiting upstream activators, such as integrins. Recent structural data demonstrated that integrin v{beta}8 can enable TGF{beta}1/3 signaling without releasing the active cytokines from their Latency-Associated Peptides, suggesting that ligand-blocking antibodies may have limited access to their epitopes. Here, we show that integrin v{beta}8 blockade, while achieving anti-tumor responses similar to those of anti-TGF{beta} antibodies, does so through a distinct mechanism of action. Anti-v{beta}8 is 3 orders of magnitude more potent at inhibiting v{beta}8-mediated TGF{beta} activity than a commonly used antibody against the mature form of the cytokine. Whereas TGF{beta} ligand inhibition has little effect on TGF{beta} signaling in tumor-draining lymph nodes (tdLN) and requires IFN{gamma} for its anti-tumor effects, v{beta}8 blockade strongly inhibits TGF{beta} signaling in tdLN and, in combination with PD-L1 blockade, drives tumor control through an IFN{gamma} -independent mechanism that strictly requires T cell egress from tdLN. Combined v{beta}8 and anti-PD-L1 blockade enhances antigen presentation in dendritic cells (DCs) and, unlike TGF{beta} ligand blockade, improves the efficiency of DC-induced T cell activation in response to cross-presented antigen. These findings suggest that v{beta}8 blockade can disable an immunologically critical source of TGF{beta} signaling that is not addressed by antibodies targeting TGF{beta} ligands, suggesting a promising new approach to TGF{beta} pathway modulation. One Sentence SummaryUnlike ligand-neutralizing antibodies, v{beta}8 blockade suppresses TGF{beta} in tdLN and boosts DC-T cell activation, a differentiated immunotherapy strategy.