Triggering CD40 on endothelial cells contributes to tumor growth

Abstract

Inflammatory cells can either promote or inhibit tumor growth. Here we studied whether CD40, a key molecule for adaptive immune response, has any role in mammary carcinogenesis of BALB/NeuT transgenic tumor-prone mice. We transferred the HER2/neu oncogene into CD40-null background to obtain the CD40-KO/NeuT strain. CD40-KO/NeuT mice showed delayed tumor onset and reduced tumor multiplicity. BM (BM) transplantation experiments excluded a role of BM-derived cells in the reduced tumorigenicity associated with CD40 deficiency. Rather, CD40 expressed by endothelial cells (ECs) takes part to the angiogenic process. Accordingly, large vessels, well organized around the tumor lobular structures, characterize BALB/NeuT tumors, whereas tiny numerous vessels with scarce extracellular matrix are dispersed in the parenchyma of poorly organized CD40-KO/NeuT tumors.Activated platelets, which may interact with and activate ECs, are a possible source of CD40L. Their localization within tumor vessels prompted the idea of treating BALB/NeuT and CD40-KO/NeuT mice chronically with the anti-platelet drug clopidogrel, known to inhibit platelet CD40L expression. Treatment of BALB/NeuT mice reduced tumor growth to a level similar to CD40-deficient mice, whereas CD40-KO/NeuT mice treated or not showed the same attenuated tumor outgrowth, indicating that activated platelets are the likely source of CD40L in this model. Collectively, these data point to a participation of CD40/CD40L in the angiogenic processes associated with mammary carcinogenesis of BALB/NeuT mice.

Activated Platelets Provide a Functional Microenvironment for the Antiangiogenic Fragment of Histidine-Rich Glycoprotein

“…Besides their role in hemostasis, platelets contribute to nonhemostatic processes such as immunity, tumor metastasis, and angiogenesis (9)(10)(11). Despite their content of both positive and negative regulators of blood vessel formation, platelets have in several different experimental settings been shown to stimulate angiogenesis (11)(12)(13)(14)(15). This apparent contradiction may be explained by recent data from Italiano and coworkers (16).…”

Vascular endothelial growth factor–induced elimination of the type 1 interferon receptor is required for efficient angiogenesis

“…18 Levels of hemoglobin and the presence of infiltrating endothelial cells in plugs were assessed as described. 19 …”

Intratumoral Delivery of TriMix mRNA Results in T-cell Activation by Cross-Presenting Dendritic Cells

“…For example, intratumoral (i.t.) delivery of TLR4 ligands induces tumor cell-resistance to cytotoxic T lymphocytes (CTL), and CD40 stimulation induces neoangiogenesis of tumor blood vessels (6,7). Consequently, strategies need to be developed that exclusively act on TiDCs, preferably on CD8a þ TiDCs, which are critical for the stimulation of antitumor immunity (8,9).…”