Stromal Macrophage Expressing CD204 is Associated with Tumor Aggressiveness in Lung Adenocarcinoma

Ohtaki, Yoichi; Ishii, Genichiro; Nagai, Kanji; Ashimine, Satoshi; Kuwata, Takeshi; Hishida, Tomoyuki; Nishimura, Mitsuyo; Takeyoshi, Izumi; Ochiai, Atsushi

doi:10.1097/jto.0b013e3181eba692

Cited by 159 publications

(151 citation statements)

References 34 publications

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“…Here, lung tissues from patients with NSCLC (adenocarcinoma, squamous cell lung carcinoma and large cell lung carcinoma) were used to investigate M1 and M2 marker expression in TAM populations within tumour and non-tumour tissue using immunohistochemistry (IHC). Various studies have demonstrated increased TAM infiltration in NSCLC using the CD68 macrophage marker [21,22,20,23,19] with some suggesting the presence of increased macrophage numbers is a powerful predictor of survival in NSCLC [19,24,9]. In our study, all NSCLC subtypes were found to have significantly more CD68-positive cells when compared to non-tumour tissues.…”

Section: Discussionsupporting

confidence: 62%

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Characterization of M1/M2 Tumour-Associated Macrophages (TAMs) and Th1/Th2 Cytokine Profiles in Patients with NSCLC

Almatroodi

McDonald

Darby

et al. 2015

Cancer Microenvironment

121

107

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Lung cancer is one of the most commonly reported cancers, and is known to be associated with a poor prognosis. The function of tumour-associated macrophages (TAMs) in lung cancer patients is multifaceted and the literature shows conflicting roles. (I) To analyze the Th1 and Th2 cytokine levels that contribute to the differentiation of M1 and M2 macrophage populations in the serum of patients with NSCLC versus non-cancer controls; and (II) To characterize the M1 and M2 macrophage populations within TAMs in different subtypes of NSCLC compared to non-tumour tissue. The Th1 and Th2 cytokine levels were analyzed in serum using the Bio-Plex assay. In addition, TAMs subsets from nontumour and tumour tissues were analyzed using immunohistochemistry (IHC). The level of IL-1β, IL-4, IL-6 and IL-8 was found to be increased in the serum of patients with large cell carcinoma but not in other NSCLC subtypes compared to non-cancer controls. In addition, the expression of CD68 and M2 marker CD163 was found to be increased (P≤0.0001) in all NSCLC subtypes compared to non-tumour tissues. In contrast, the expression of iNOS (M1 marker) was decreased in the tumour tissue of patients with adenocarcinoma (P≤0.01) and squamous carcinoma (P≤0.05) but not in large cell carcinoma compared to non-tumour tissue. The results of this study indicate that NSCLC might have the ability to alter phenotype within the lung tumour areas in the local environment (TAMs) but not in the bloodstream in the systemic environment (serum) except for large cell carcinoma.

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Section: Discussionsupporting

confidence: 62%

“…Also, the CD68 + and CD163 + TAMs count was found to be significantly increased in patients with progressive disease [33]. Furthermore, other studies have shown that the expression of the M2 marker in TAMs was significantly correlated to poor prognosis, p-TNM staging and lymph node metastasis in patients with advanced adenocarcinoma [22,32].…”

Section: Discussionmentioning

confidence: 79%

Characterization of M1/M2 Tumour-Associated Macrophages (TAMs) and Th1/Th2 Cytokine Profiles in Patients with NSCLC

Almatroodi

McDonald

Darby

et al. 2015

Cancer Microenvironment

121

107

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“…21,22 Nevertheless, the fact that the majority of TAMs localize in the tumor stroma 2 and express protumor M2 markers 20 still supports a protumor role of TAMs in most NSCLC patients, as observed in earlier studies. 18,19 Furthermore, this is supported by a recent report from Ohtaki et al, 23 who demonstrated an association between CD204-positive stromal macrophages and poor outcomes, indicating the protumor effect of stromal macrophages.…”

Section: Introductionmentioning

confidence: 69%

Tumor‐associated macrophages correlate with response to epidermal growth factor receptor‐tyrosine kinase inhibitors in advanced non‐small cell lung cancer

Chung

Lee

Wang

et al. 2012

Intl Journal of Cancer

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Our study investigated whether tumor-associated macrophages (TAMs) in advanced non-small cell lung cancer (NSCLC) are related to treatment response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and may be a predictor of survival. Of 206 advanced NSCLC patients treated (first-line) with an EGFR-TKI at the study hospital from 2006 to 2009, 107 with adequate specimens for assessing CD68 immunohistochemistry as a marker of TAMs were assessed. After EGFR-TKI treatment, response was observed in 55 (51%) patients, and the median follow-up period was 13.5 months. Most TAMs were located in the tumor stroma (>95%) and positively costained with the M2 marker CD163. TAM counts were significantly higher in patients with progressive disease than in those without (p < 0.0001), a trend that remained in patients with known EGFR mutation status (n 5 59) and those with wild-type EGFR (n 5 20). High TAM counts, among other factors (e.g., wild-type EGFR), were significantly related to poor progression-free survival (PFS) and overall survival (OS) (all p < 0.0001 for TAMs). Multivariate Cox analyses showed that high TAM counts and EGFR mutations were both independent factors associated with PFS [odds ratio (OR), 8.0; 95% confidence interval (CI), 2.87-22.4; p 5 0.0001 and OR, 0.03; 95% CI, 0.003-0.31; p 5 0.003, respectively] and OS (OR, 2.641; 95% CI, 1.08-6.5; p 5 0.03 and OR, 0.14; 95% CI, 0.03-0.56; p 5 0.006, respectively). TAMs are related to treatment response irrespective of EGFR mutation and can independently predict survival in advanced NSCLC treated with an EGFR-TKI.

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“…TAMs are one of the major immunosuppressive cells affecting the tumor microenvironment able to influence tumor progression and the success or failure of immunotherapy, 26 and emerging evidence reveals a significant correlation between high TAM numbers and poor patient prognoses in lung cancer patients.In advanced NSCLC patients treated (first-line) with an EGFR-TKI, M2-polarized counts was associated with a marked decrease in treatment response 27 and correlated with lymph node metastasis and poor prognosis. 28,29 Moreover, several studies have suggested a role for the expression of the immunosuppressive cytokine IL-10 by TAMs in the progression and prognosis of NSCLC. 30,31 We found that the addition of Poly(I:C) to aerosolized CpG-ODN resulted in increased antitumor activity in mice bearing B16 lung metastases as compared to mice treated with either aerosolized agonist alone.…”

Section: Discussionmentioning

confidence: 99%

Poly(I:C) and CpG-ODN combined aerosolization to treat lung metastases and counter the immunosuppressive microenvironment

et al. 2015

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The immunostimulatory ability of synthetic oligonucleotides containing CpG motifs (CpG-ODN), agonists of Toll-like receptor 9 (TLR9), can be harnessed to promote antitumor immunity by their application at the tumor site to stimulate local activation of innate immunity; however, particularly in the lung, tumor-associated immunosuppression can subvert such antitumor innate immune responses. To locally maintain continuous activation of innate subpopulations while inhibiting immunosuppressive cells, we evaluated aerosol delivery CpG-ODN combined with Poly(I:C), a TLR3 agonist able to convert tumor-supporting macrophages to tumoricidal effectors, in the treatment of B16 melanoma lung metastases in C57BL/6 mice. Aerosolization of CpG-ODN with Poly(I:C) into the bronchoalveolar space reduced the presence of M2-associated arginase-and IL-10-secreting macrophages in tumor-bearing lungs and increased the antitumor activity of aerosolized CpG-ODN alone against B16 lung metastases without apparent signs of toxicity or injury of the bronchial-bronchiolar structures and alveolar walls. Moreover, CpG-ODN/Poly(I:C) aerosol combined with dacarbazine, a therapeutic agent used in patients with inoperable metastatic melanoma able to exert immunostimulatory effects, led to a significant increase in antitumor activity as compared to treatments with aerosolized CpG-ODN/Poly(I:C) or dacarbazine alone. This effect was related to an enhanced recruitment and cytotoxic activity of tumor-infiltrating NK cells in the lung. Our results point to aerosol delivery as a convenient approach for repeated applications of immunostimulants in patients with lung metastases to maintain a continuous local activation of innate immune cells while suppressing polarization of tumor-infiltrating macrophages to an M2 phenotype.

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Stromal Macrophage Expressing CD204 is Associated with Tumor Aggressiveness in Lung Adenocarcinoma

Cited by 159 publications

References 34 publications

Characterization of M1/M2 Tumour-Associated Macrophages (TAMs) and Th1/Th2 Cytokine Profiles in Patients with NSCLC

Characterization of M1/M2 Tumour-Associated Macrophages (TAMs) and Th1/Th2 Cytokine Profiles in Patients with NSCLC

Tumor‐associated macrophages correlate with response to epidermal growth factor receptor‐tyrosine kinase inhibitors in advanced non‐small cell lung cancer

Poly(I:C) and CpG-ODN combined aerosolization to treat lung metastases and counter the immunosuppressive microenvironment

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