Macrophage Diversity Enhances Tumor Progression and Metastasis

Macrophages are crucial drivers of tumour-promoting inflammation. Tumour-associated macrophages (TAMs) contribute to tumour progression at different levels: by promoting genetic instability, nurturing cancer stem cells, supporting metastasis, and taming protective adaptive immunity. TAMs can exert a dual, yin-yang influence on the effectiveness of cytoreductive therapies (chemotherapy and radiotherapy), either antagonizing the antitumour activity of these treatments by orchestrating a tumour-promoting, tissue-repair response or, instead, enhancing the overall antineoplastic effect. TAMs express molecular triggers of checkpoint proteins that regulate T-cell activation, and are targets of certain checkpoint-blockade immunotherapies. Other macrophage-centred approaches to anticancer therapy are under investigation, and include: inhibition of macrophage recruitment to, and/or survival in, tumours; functional re-education of TAMs to an antitumour, 'M1-like' mode; and tumour-targeting monoclonal antibodies that elicit macrophage-mediated extracellular killing, or phagocytosis and intracellular destruction of cancer cells. The evidence supporting these strategies is reviewed herein. We surmise that TAMs can provide tools to tailor the use of cytoreductive therapies and immunotherapy in a personalized medicine approach, and that TAM-focused therapeutic strategies have the potential to complement and synergize with both chemotherapy and immunotherapy.

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Tumour-associated macrophages as treatment targets in oncology

Macrophages are prominent in the stromal compartment of virtually all types of malignancy. These highly versatile cells respond to the presence of stimuli in different parts of tumors with the release of a distinct repertoire of growth factors, cytokines, chemokines, and enzymes that regulate tumor growth, angiogenesis, invasion, and/or metastasis. The distinct microenvironments where tumor-associated macrophages (TAM) act include areas of invasion where TAMs promote cancer cell motility, stromal and perivascular areas where TAMs promote metastasis, and avascular and perinecrotic areas where hypoxic TAMs stimulate angiogenesis. This review will discuss the evidence for differential regulation of TAMs in these microenvironments and provide an overview of current attempts to target or use TAMs for therapeutic purposes. (Cancer Res 2006; 66(2): 605-12)

https://cancerres.aacrjournals.org/content/canres/66/2/605.full.pdf

Distinct Role of Macrophages in Different Tumor Microenvironments

Background Despite advances in treatments for Hodgkin's lymphoma, about 20% of patients still die from progressive disease. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on the International Prognostic Score. Methods Using gene-expression profiling, we analyzed 130 frozen samples obtained from patients with classic Hodgkin's lymphoma during diagnostic lymph-node biopsy to determine which cellular signatures were correlated with treatment outcome. We confirmed our findings in an independent cohort of 166 patients, using immunohistochemical analysis. Results Gene-expression profiling identified a gene signature of tumor-associated macrophages that was significantly associated with primary treatment failure (P=0.02). In an independent cohort of patients, we found that an increased number of CD68+ macrophages was correlated with a shortened progression-free survival (P=0.03) and with an increased like...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0905680

Tumor-Associated Macrophages and Survival in Classic Hodgkin's Lymphoma

Purpose The aim of the F2 study was to verify whether a prospective collection of data would enable the development of a more accurate prognostic index for follicular lymphoma (FL) by using parameters which could not be retrospectively studied before, and by choosing progression-free survival (PFS) as principal end point. Patients and Methods

https://ascopubs.org/doi/pdf/10.1200/JCO.2008.21.3991

Follicular Lymphoma International Prognostic Index 2: A New Prognostic Index for Follicular Lymphoma Developed by the International Follicular Lymphoma Prognostic Factor Project

Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL)

Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: the British Columbia experience

Limited-stage mantle-cell lymphoma

Mycosis fungoides (MF) and its leukemic variant, Sezary syndrome (SS), are the most common cutaneous T-cell lymphomas, with a combined incidence of 0.36 of 100,000 person-years. Although thought to be closely related to mature T-helper cells, the true nature of the cancer cells in MF/SS is unknown. In addition, there is no known specific marker for MF/SS cancer cells, which can result in difficulties in the diagnosis and treatment. To identify MF/SS-specific markers, Sezary cancer cells were analyzed with a global genomic screening tool, the modified representational difference analysis. It was discovered that unlike T-helper cells from healthy individuals or patients with nonmalignant dermatoses, Sezary cells from most patients with Sezary syndrome aberrantly expressed T-plastin mRNA and protein. This is the first time T-plastin protein, a cytoplasmic protein regulating actin assembly and cellular motility, has been detected in the hematopoietic cells. Therefore, T-plastin has the potential to be a Sezary cell-specific marker valuable for diagnostic and treatment of Sezary syndrome.

https://cancerres.aacrjournals.org/content/canres/63/21/7122.full.pdf

N. J. Voss

Papers

Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL)

Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: the British Columbia experience

Limited-stage mantle-cell lymphoma

Aberrant expression of T-plastin in Sezary cells.

Primary therapy for adults with T-cell lymphoblastic lymphoma with hematopoietic stem-cell transplantation results in favorable outcomes