Modulation of Tumor-Associated Macrophages (TAM) Phenotype by Platelet-Activating Factor (PAF) Receptor

Abstract

Platelet-activating factor (PAF) plays an important role in the pathogenesis of several types of tumors. The biological effects of PAF are mediated by the PAF receptor (PAFR), which can be expressed by tumor cells and host cells that infiltrate the tumor microenvironment. In the present study, we investigated the role of PAFR expressed by leukocytes that infiltrate two types of tumors, one that expresses PAFR (TC-1 carcinoma) and another that does not express the receptor (B16F10 melanoma) implanted in mice that express the receptor or not (PAFR KO). It was found that both tumors grew significantly less in PAFR KO than in wild-type (WT) mice. Analysis of the leukocyte infiltration shown in PAFR KO increased the frequency of neutrophils (Gr1+) and of CD8+ lymphocytes in B16F10 tumors and of CD4+ lymphocytes in TC-1 tumors. PAFR KO also had a higher frequency of M1-like (CD11c+) and lower M2-like (CD206+) macrophages infiltrated in both tumors. This was confirmed in macrophages isolated from the tumors that showed higher iNOS, lower arginase activity, and lower IL10 expression in PAFR KO tumors than WT mice. These data suggest that in the tumor microenvironment, endogenous PAF-like activity molecules bind PAFR in macrophages which acquire an M2-like profile and this promotes tumor growth.

Platelet activating factor receptor antagonists improve the efficacy of experimental chemo- and radiotherapy

“…We found that two types of murine tumors, B16F10 melanoma and TC-1 carcinoma, showed significantly less growth in mice genetically deficient for PAFR (PAFRKO) than in wild type (WT) mice. This change occurred in parallel with the increased frequency of neutrophils and CD4 + /CD8 + lymphocyte infiltration in the tumors implanted in PAFRKO, suggesting that PAFR may be involved in the recruitment of these cells into the tumor stroma 38 . Macrophages undergo functional and phenotypic changes in response to signals from the tumor microenvironment.…”

“…Moreover, when we analyzed the macrophages infiltrated in the tumors on day 15, the PAFKO mice had a higher frequency of M1-like macrophages (CD11c + ; high iNOS; low arginase; low IL10) than WT mice, whereas those from WT mice presented the M2 phenotype marker (CD206 + ). Thus, in the absence of PAFR, the tumor infiltrating macrophages acquire an activated phenotype, which is associated with the reduced tumor growth observed in PAF KO animals 38 , suggesting that PAFR activation reprograms macrophages towards the M2 phenotype in experimental tumors.…”

Physiological Roles of Mast Cells: Collegium Internationale Allergologicum Update 2019

“…Histamine (H 1 and H 2 receptors) [30], cysteinyl leukotriene D 4 (LTD 4 ) [31], platelet-activating factor (PAF) [32], and vascular endothelial growth factor A (VEGF-A) [33] modulate the functions of monocytes. Mast cells interact with macrophages through the release of histamine (H 1 , H 2 , and H 3 receptors) [34, 35], IL-6 [36], IL-13 [37], PGD 2 [38], and PAF [32]. PGD 2 [39], PGE 2 [40], VEGF-C [41], and histamine (H 1 and H 2 ) [42, 43] influence the activity of dendritic cells.…”

Systemic Platelet-Activating Factor-Receptor Agonism Enhances Non-Melanoma Skin Cancer Growth

“…The stability of PAF-R agonists is regulated by PAF metabolizing enzymes, PAF-acetyl hydrolases (PAF-AH), which are found in multiple cell types and lipoproteins [ 3 , 4 ]. Studies, including ours, have shown that enzymatic (i.e., PAF) or non-enzymatically (e.g., ultraviolet B (UVB), cigarette smoke, jet fuel, and tumor promoters, such as PMA) generated PAF-R agonists mediate various pathophysiological effects, including enhanced growth of tumors in experimental models [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. In particular, tumor growth promoting effects can be mimicked by the administration of a non-metabolizable form of PAF (1-hexadecyl-2- N -methyl carbamoyl glycerophosphocholine (CPAF)) [ 7 , 19 ].…”

“…Given the intriguing roles of PAF-R agonists in modulating the growth of experimental melanoma and NMSC in response to diverse stimuli [ 7 , 15 , 19 , 23 , 24 , 25 , 26 ], the current study was designed to determine if systemic PAF-R agonist exposure modulates DMBA/PMA-induced cutaneous carcinogenesis. Our study took advantage of a recent report by Nasti et al, which characterized a DMBA/PMA cutaneous carcinogenesis model [ 27 ] in C3H/HeN mice that induces both NMSC and melanocytic nevi, which in turn can be transformed into malignant melanoma [ 28 ].…”