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Checkpoint-inhibitor (CPI) immunotherapy has achieved remarkable clinical success, yet its efficacy in ‘immunologically cold’ tumours has been modest. Interleukin-12 (IL-12) is a powerful cytokine that activates the innate and adaptive arms of the immune system; however, the administration of IL-12 has been associated with immune-related adverse events. Here we show that, after intravenous administration of a collagen-binding domain fused to IL-12 (CBD–IL-12) in mice bearing aggressive mouse tumours, CBD–IL-12 accumulates in the tumour stroma due to exposed collagen in the disordered tumour vasculature. In comparison with the administration of unmodified IL-12, CBD–IL-12 induced sustained intratumoural levels of interferon-γ, substantially reduced its systemic levels as well as organ damage and provided superior anticancer efficacy, eliciting complete regression of CPI-unresponsive breast tumours. Furthermore, CBD–IL-12 potently synergized with CPI to eradicate large established melanomas, induced antigen-specific immunological memory and controlled tumour growth in a genetically engineered mouse model of melanoma. CBD–IL-12 may potentiate CPI immunotherapy for immunologically cold tumours. A collagen-binding interleukin-12 formulation intravenously injected into mice bearing established immunologically cold mouse tumours led to marked tumour remission, particularly when combined with checkpoint-inhibitor immunotherapy.

BackgroundVascular endothelial growth factor-C (VEGF-C) expression and subsequent lymphangiogenesis in the tumor microenvironment are associated with metastasis and poor prognosis in melanoma and other solid tumors. We previously demonstrated that while elevated VEGF-C promotes a highly immunosuppressive tumor microenvironment (TME), it paradoxically renders immunotherapy more effective in mouse models and correlates with improved survival after checkpoint blockade therapy in patients, a phenomenon we termed lymphangiogenic potentiation.1 This potentiation correlated with VEGFC-driven differences in the TME prior to immunotherapy, including increased recruitment of naïve T cells and cross-presenting CD103+ DCs in VEGFC-overexpressing tumors, setting up the TME for local T cell activation .Other than altering the TME, tumor lymphangiogenesis may alter the systemic immune response because of increased drainage of tumor-secreted factors, which may include both immunogenic and suppressive factors, to the tumor-draining lymph node (tdLN). Here, we asked whether and how these changes may contribute to the overall immune response as well as how the anti-tumor immune response can alter the TME in melanoma.MethodsWe used a B16F10 tumor model transduced to either overexpress VEGFC (B16-VEGFC) or a control vector (B16-Control) together with two different models of immunotherapy: (i) adoptive T cell transfer and (ii) peptide vaccination using transferred naïve antigen-specific pmel CD8+ T cells for in vivo tracking after activation by gp100 peptide and CpG adjuvant.ResultsWe found that immunotherapy resulted in an increase targeted antigen-specific T cells in the B16-VEGFC vs. B16-Control tumors, including more proliferating effector cells as well as more central memory and T progenitor exhausted cells. We also found more bystander activation and proliferation of non-targeted, endogenous CD8 T cells. This was accompanied by an increase in CXCL9 in the TME of B16-VEGFC, which recruited more activated T cells from circulation. In the B16-VEGFC tdLN, we observed increased in CD103+ DC trafficking along with higher fractions of central memory T cells in both the CD4 and CD8 compartments.ConclusionsTogether, these results highlight the multitude of ways that tumor lymphangiogenesis can prime anti-tumor immunity and alter not only the tumor microenvironment, but also the systemic immune response by shaping the immune microenvironment of the tumor draining lymph node. VEGFC tumors promote more prolonged immunity after immunotherapy by supporting T cell memory development and enhancing ongoing immune activation and recruitment through increased DC trafficking to the lymph node and increased recruitment of newly activated and circulating T cells.ReferenceFankhauser M. Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma. Sci. Transl. Med. 2017;9:eaa14712.

In allergic airway inflammation, VEGFR-3-mediated lymphangiogenesis occurs in humans and mouse models, yet its immunological roles, particularly in adaptive immunity, are poorly understood. Here, we explored how pro-lymphangiogenic signaling affects the allergic response to house dust mite (HDM). In the acute inflammatory phase, the lungs of mice treated with blocking antibodies against VEGFR-3 (mF4-31C1) displayed less inflammation overall, with dramatically reduced innate and T-cell numbers and reduced inflammatory chemokine levels. However, when inflammation was allowed to resolve and memory recall was induced 2 months later, mice treated with mF4-31C1 as well as VEGF-C/-D knockout models showed exacerbated type 2 memory response to HDM, with increased Th2 cells, eosinophils, type 2 chemokines, and pathological inflammation scores. This was associated with lower CCL21 and decreased TRegs in the lymph nodes. Together, our data imply that VEGFR-3 activation in allergic airways helps to both initiate the acute inflammatory response and regulate the adaptive (memory) response, possibly in part by shifting the TReg/Th2 balance. This introduces new immunomodulatory roles for pro-lymphangiogenic VEGFR-3 signaling in allergic airway inflammation and suggests that airway lymphatics may be a novel target for treating allergic responses.

Checkpoint inhibitor (CPI) immunotherapy has achieved remarkable clinical success, yet its efficacy in ‘immunologically cold’ tumours has been modest. Interleukin (IL)-12 is a powerful cytokine that activates the innate and adaptive arms of the immune system, yet its administration has been associated with immune-related adverse events. Here, we show that the intravenous administration of a collagen-binding domain fused to IL-12 (CBD–IL-12) in mice bearing aggressive murine tumours accumulates in the tumour stroma, owing to exposed collagen in the disordered tumour vasculature. In comparison with the administration of unmodified IL-12, CBD–IL-12 induced sustained intratumoral levels of interferon-γ, markedly reduced its systemic levels as well as organ damage, and led to superior anticancer efficacy, eliciting complete regression of CPI-unresponsive breast tumours. Furthermore, CBD–IL-12 potently synergized with CPI to eradicate large established melanoma, induced antigen-specific immunological memory, and controlled tumour growth in a genetically engineered mouse model of melanoma. CBD–IL-12 may potentiate CPI immunotherapy for immunologically cold tumours.