2015 Fiscal Year Research-status Report
Colony stimulating factor 1 receptor (CSF1R) and immune regulatory M2c-like tumor associated macrophages (TAMs) in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma transformation (tFL)
| Project/Area Number |
15K19061
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| Research Institution | Tokai University |
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Principal Investigator |
カレーラス ジュアキム 東海大学, 医学部, 講師 (90637191)
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| Project Period (FY) |
2015-04-01 – 2017-03-31
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| Keywords | CSF1R / 腫瘍関連マクロファージ / 濾胞性リンパ腫 / びまん性大細胞型B細胞リンパ腫 / 血液病理学 / 免疫組織化学 |
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| Outline of Annual Research Achievements |
We aimed to elucidate the role of CSF1R and M2-like Tumor Associated Macrophages (TAMs) in de novo Diffuse Large B-cell Lymphoma (DLBCL) and Follicular Lymphoma (FL).
We analyzed CSF1R pathway in 109 cases of de novo DLBCL by immunohistochemical and digital analysis on CSF1R, CSF1, STAT3, NF－KB, MYC and Ki67, including 3D cell marker localization. The markers showed a right－skewed distributions. No correlation was found with most of the clinical variables except for CSF1R. Mean CSF1R expression was 25％±25.3 with bimodal distribution (at 60％ cutoff the TAMs vs B cell expression patterns were differentiated). CSF1R conferred prognostic relevance: CSF1R＋B cell pattern was associated with favorable prognosis [5 year PFS of 87％ (P＝0.018); HR of 0.1 (P＝0.032)] while CSF1R＋TAM pattern to unfavorable prognosis[5 year PFS of 53％ (P＝0.018); HR of 4.7 (P＝0.032)].
We also studied microenvironment markers in DLBCL and FL. FL series was comprised of 26 FL (low grade, 13; high grade 3a, 7; 3b, 3; and transformed FL, 3). Immunohistochemistry focused on pan-TAMs (CD68), M1-like TAMs (CD16), M2-like TAMs (CSF1R, CD163, PTX3, MITF, CCR2 and CSF1) and FOXP3+Tregs.In comparison to DLBCL, FL is characterized by lower expression of CD68, CD16, CD163, MITF and FOXP3 (P<0.05). Progression of FL towards tFL is characterized by progressive increase of CD68, CSF1R, CD163 and MITF (P<0.05).
Of note, sinonasal DLBCL has also been investigated for CSF1R.
In conclusion, CSF1Ris relevant for the prognosis of de novo DLBCL as well as for the FL progression and transformation to DLBCL.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
The progress of the project is rather smooth and we have already achieved most of the planned aims.
The immunohistochemistry of some markers of CSF1R pathway such as STAT5, CSF1 and HIF1 are difficult to interpret due to their wide range of expression in different cell populations. The staining for IL10, which is an important immune regulatory marker candidate in our project, is also difficult; so far we have tried 3 different antibody clones but we still fail to identify specific staining in macrophages neither in benign and tumoral lymphoid tissue.
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| Strategy for Future Research Activity |
1) Increase the number of cases of the series of DLBCL as well as FL in order to increase the power of the statistical analysis. We would like to reach the 200 cases in total for DLBCL and around 100 for FL.
2) Add new markers to be analyzed by immunohistochemistry that may allow to further characterize the CSF1R pathway as well as to subclassify the M2-like TAMs into M2a, M2b and M2c and differentiate from M1 polarization.
3) In vitro analysis with DLBCL cell lines or genomic profile-gene expression of the most characteristic cases associated with unfavorable prognosis.
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