Spatial Metrics of Interaction between CD163-Positive Macrophages and Cancer Cells and Progression-Free Survival in Chemo-Treated Breast Cancer
Tumor-associated macrophages (TAMs) promote progression of breast cancer and other solid malignancies via immunosuppressive, pro-angiogenic and pro-metastatic effects. Tumor-promoting TAMs tend to express M2-like macrophage markers, including CD163. Histopathological assessments suggest that the den...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/2/308 |
| _version_ | 1797495313806655488 |
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| author | Brenton A. Maisel Misung Yi Amy R. Peck Yunguang Sun Jeffrey A. Hooke Albert J. Kovatich Craig D. Shriver Hai Hu Marja T. Nevalainen Takemi Tanaka Nicole Simone Li Lily Wang Hallgeir Rui Inna Chervoneva |
| author_facet | Brenton A. Maisel Misung Yi Amy R. Peck Yunguang Sun Jeffrey A. Hooke Albert J. Kovatich Craig D. Shriver Hai Hu Marja T. Nevalainen Takemi Tanaka Nicole Simone Li Lily Wang Hallgeir Rui Inna Chervoneva |
| author_sort | Brenton A. Maisel |
| collection | DOAJ |
| description | Tumor-associated macrophages (TAMs) promote progression of breast cancer and other solid malignancies via immunosuppressive, pro-angiogenic and pro-metastatic effects. Tumor-promoting TAMs tend to express M2-like macrophage markers, including CD163. Histopathological assessments suggest that the density of CD163-positive TAMs within the tumor microenvironment is associated with reduced efficacy of chemotherapy and unfavorable prognosis. However, previous analyses have required research-oriented pathologists to visually enumerate CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> TAMs, which is both laborious and subjective and hampers clinical implementation. Objective, operator-independent image analysis methods to quantify TAM-associated information are needed. In addition, since M2-like TAMs exert local effects on cancer cells through direct juxtacrine cell-to-cell interactions, paracrine signaling, and metabolic factors, we hypothesized that spatial metrics of adjacency of M2-like TAMs to breast cancer cells will have further information value. Immunofluorescence histo-cytometry of CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> TAMs was performed retrospectively on tumor microarrays of 443 cases of invasive breast cancer from patients who subsequently received adjuvant chemotherapy. An objective and automated algorithm was developed to phenotype CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> TAMs and calculate their density within the tumor stroma and derive several spatial metrics of interaction with cancer cells. Shorter progression-free survival was associated with a high density of CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> TAMs, shorter median cancer-to-CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> nearest neighbor distance, and a high number of either directly <i>adjacent</i> CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> TAMs (within juxtacrine proximity <12 μm to cancer cells) or <i>communicating</i> CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> TAMs (within paracrine communication distance <250 μm to cancer cells) after multivariable adjustment for clinical and pathological risk factors and correction for optimistic bias due to dichotomization. |
| first_indexed | 2024-03-10T01:47:03Z |
| format | Article |
| id | doaj.art-4cf41e42250e412bb1455820ab49682f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T01:47:03Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-4cf41e42250e412bb1455820ab49682f2023-11-23T13:12:49ZengMDPI AGCancers2072-66942022-01-0114230810.3390/cancers14020308Spatial Metrics of Interaction between CD163-Positive Macrophages and Cancer Cells and Progression-Free Survival in Chemo-Treated Breast CancerBrenton A. Maisel0Misung Yi1Amy R. Peck2Yunguang Sun3Jeffrey A. Hooke4Albert J. Kovatich5Craig D. Shriver6Hai Hu7Marja T. Nevalainen8Takemi Tanaka9Nicole Simone10Li Lily Wang11Hallgeir Rui12Inna Chervoneva13Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USAJohn P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD 20814, USAJohn P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD 20814, USAJohn P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD 20814, USAChan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, PA 15963, USADepartment of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Pathology, University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma City, OK 73104, USADepartment of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USADepartment of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USADepartment of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USATumor-associated macrophages (TAMs) promote progression of breast cancer and other solid malignancies via immunosuppressive, pro-angiogenic and pro-metastatic effects. Tumor-promoting TAMs tend to express M2-like macrophage markers, including CD163. Histopathological assessments suggest that the density of CD163-positive TAMs within the tumor microenvironment is associated with reduced efficacy of chemotherapy and unfavorable prognosis. However, previous analyses have required research-oriented pathologists to visually enumerate CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> TAMs, which is both laborious and subjective and hampers clinical implementation. Objective, operator-independent image analysis methods to quantify TAM-associated information are needed. In addition, since M2-like TAMs exert local effects on cancer cells through direct juxtacrine cell-to-cell interactions, paracrine signaling, and metabolic factors, we hypothesized that spatial metrics of adjacency of M2-like TAMs to breast cancer cells will have further information value. Immunofluorescence histo-cytometry of CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> TAMs was performed retrospectively on tumor microarrays of 443 cases of invasive breast cancer from patients who subsequently received adjuvant chemotherapy. An objective and automated algorithm was developed to phenotype CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> TAMs and calculate their density within the tumor stroma and derive several spatial metrics of interaction with cancer cells. Shorter progression-free survival was associated with a high density of CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> TAMs, shorter median cancer-to-CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> nearest neighbor distance, and a high number of either directly <i>adjacent</i> CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> TAMs (within juxtacrine proximity <12 μm to cancer cells) or <i>communicating</i> CD<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mn>163</mn><mo>+</mo></msup></semantics></math></inline-formula> TAMs (within paracrine communication distance <250 μm to cancer cells) after multivariable adjustment for clinical and pathological risk factors and correction for optimistic bias due to dichotomization.https://www.mdpi.com/2072-6694/14/2/308tumor-associated macrophagescancer biomarkerstumor immune microenvironmentspatially-resolved immunohistochemistry datamarked point patternsnearest neighbor distance |
| spellingShingle | Brenton A. Maisel Misung Yi Amy R. Peck Yunguang Sun Jeffrey A. Hooke Albert J. Kovatich Craig D. Shriver Hai Hu Marja T. Nevalainen Takemi Tanaka Nicole Simone Li Lily Wang Hallgeir Rui Inna Chervoneva Spatial Metrics of Interaction between CD163-Positive Macrophages and Cancer Cells and Progression-Free Survival in Chemo-Treated Breast Cancer Cancers tumor-associated macrophages cancer biomarkers tumor immune microenvironment spatially-resolved immunohistochemistry data marked point patterns nearest neighbor distance |
| title | Spatial Metrics of Interaction between CD163-Positive Macrophages and Cancer Cells and Progression-Free Survival in Chemo-Treated Breast Cancer |
| title_full | Spatial Metrics of Interaction between CD163-Positive Macrophages and Cancer Cells and Progression-Free Survival in Chemo-Treated Breast Cancer |
| title_fullStr | Spatial Metrics of Interaction between CD163-Positive Macrophages and Cancer Cells and Progression-Free Survival in Chemo-Treated Breast Cancer |
| title_full_unstemmed | Spatial Metrics of Interaction between CD163-Positive Macrophages and Cancer Cells and Progression-Free Survival in Chemo-Treated Breast Cancer |
| title_short | Spatial Metrics of Interaction between CD163-Positive Macrophages and Cancer Cells and Progression-Free Survival in Chemo-Treated Breast Cancer |
| title_sort | spatial metrics of interaction between cd163 positive macrophages and cancer cells and progression free survival in chemo treated breast cancer |
| topic | tumor-associated macrophages cancer biomarkers tumor immune microenvironment spatially-resolved immunohistochemistry data marked point patterns nearest neighbor distance |
| url | https://www.mdpi.com/2072-6694/14/2/308 |
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