Surfactant Protein A Suppresses Lung Cancer Progression by Regulating the Polarization of Tumor-Associated Macrophages

Abstract

Surfactant protein A (SP-A) is a large multimeric protein found in the lungs. In addition to its immunoregulatory function in infectious respiratory diseases, SP-A is also used as a marker of lung adenocarcinoma. Despite the finding that SP-A expression levels in cancer cells has a relationship with patient prognosis, the function of SP-A in lung cancer progression is unknown. We investigated the role of SP-A in lung cancer progression by introducing the SP-A gene into human lung adenocarcinoma cell lines. SP-A gene transduction suppressed the progression of tumor in subcutaneous xenograft or lung metastasis mouse models. Immunohistochemical analysis showed that the number of M1 antitumor tumor-associated macrophages (TAMs) was increased and the number of M2 tumor-promoting TAMs was not changed in the tumor tissue produced by SP-Aeexpressing cells. In addition, natural killer (NK) cells were also increased and activated in the SP-Aeexpressing tumor. Moreover, SP-A did not inhibit tumor progression in mice depleted of NK cells. Taking into account that SP-A did not directly activate NK cells, these results suggest that SP-A inhibited lung cancer progression by recruiting and activating NK cells via controlling the polarization of TAMs. (Am J Pathol 2013 http:// dx

IκB Kinase Activity Drives Fetal Lung Macrophage Maturation along a Non-M1/M2 Paradigm

“…The notion of M1/M2 macrophage polarization derives largely from studies using tumor-associated macrophages and chronic inflammation models(36-38). So while activation of M1 macrophages and M2 polarization may contribute to disease, this classification paradigm may not directly apply to the developmental phenotypes of lung macrophages.…”

Morphofunctional Characteristics of Pulmonary Surfactant System and Its Effect on Immune Cells in Influenza A (H1N1) Pathogenesis

“…Surfactant protein SP-A is one of the factors that controls the M1 polarization. SP-A increases macrophage recruitment, phagocytic and secretory activity, including the production of NOsynthases [21] [22] (Figure 3).…”

Identification of CD245 as myosin 18A, a receptor for surfactant A: A novel pathway for activating human NK lymphocytes

“…21 SP-A has also been shown to strongly stimulate the anti-tumor immunity in a xenograft mouse model. 19 Tumor cells transduced with SP-A grew slower than those transduced with the vector alone. This antitumor effect of SP-A was entirely dependent on NK cells in vivo 19 although the exact mechanism remained unknown.…”

“…19 Tumor cells transduced with SP-A grew slower than those transduced with the vector alone. This antitumor effect of SP-A was entirely dependent on NK cells in vivo 19 although the exact mechanism remained unknown. We showed that myosin 18A/CD245 is a potent human NK cell co-activating receptor, whose cell surface expression is increased by IL-2.…”

“…19 This antitumor effect of SP-A was dependent on NK cells in vivo 19 although the exact mechanisms remained unknown. To address this issue, we investigated whether the engagement of CD245 was able to modulate the NK cell redirected cytotoxicity against the murine mastocytoma cell line P815.…”