Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy

Area of Science:

• Immunology
• Oncology
• Vascular Biology

Background:

• Solid tumors exhibit inherent resistance to immune responses.
• Abnormal tumor vasculature impedes immune cell infiltration, contributing to immune suppression.
• Pancreatic neuroendocrine tumors (PNETs) present a challenge for effective immunotherapy.

Purpose of the Study:

• To investigate the effects of interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) on immune suppression within PNETs.
• To determine if targeting these cytokines can enhance anti-tumor immunity and improve therapeutic outcomes.
• To elucidate the mechanisms by which these cytokines modulate tumor vasculature and immune cell trafficking.

Main Methods:

• Intratumoral administration of IFNγ and low-dose TNFα in a PNET model.
• Assessment of immune cell infiltration (specifically CD8(+) T cells) and tumor vascularization.
• Analysis of vessel integrity, perfusion, and macrophage reprogramming.
• Evaluation of therapeutic efficacy in combination with antitumor vaccination or adoptive T-cell therapy.

Main Results:

• Intratumoral IFNγ led to rapid vessel loss, hindering anti-tumor immunity.
• Low-dose TNFα significantly enhanced CD8(+) T-cell infiltration and improved overall survival.
• TNFα stabilized the vascular network and improved perfusion, without increasing vessel leakiness.
• Tumor-resident macrophages were reprogrammed by TNFα to modulate immune and angiogenic factors.
• Combined TNFα therapy with immunotherapy substantially improved treatment outcomes.

Conclusions:

• Low-dose TNFα effectively remodels tumor vasculature to facilitate immune cell infiltration.
• TNFα enhances anti-tumor immune responses mediated by CD8(+) effector cells.
• This cytokine acts as a potent adjuvant, significantly improving the efficacy of antitumor vaccination and adoptive T-cell therapy.