Review Plasticity beyond Cancer Cells and the "Immunosuppressive Switch" Zvi Granot 1 and Zvi G. Fridlender 2 Abstract Tumor initiation, growth, and metastatic progression are complex processes that, in order to be successful, require extraordinary cellular plasticity. Accordingly, tumor cell plas- ticity and how it affects disease progression have been studied extensively. However, as our understanding of the tumor microenvironment deepens, we are confronted with the notion that functional plasticity in the context of cancer is not limited to tumor cells alone but is also commonly seen in normal stromal cells of the microenvironment, and specifically in immune cells. Here, we review the functional plasticity these cells exhibit in the context of cancer, highlighting the role of circulating and tumor-associated neutrophils. We further dis- cuss how this plasticity supports or limits tumor progression, inducing an "immunosuppressive switch" to promote further tumor growth and development. Cancer Res; 75(21); 4441–5. Ó2015 AACR. Introduction In the past several decades, much attention has been directed toward understanding how tumors grow and progress. Cancer research has focused on an in-depth characterization of tumor cells toward identifying weaknesses that could be exploited ther- apeutically. Most of the research was aimed at understanding tumor cell autonomous features that make a tumor—prolifera- tion, avoiding cell death, acquiring migratory properties, etc. However, in recent years, it has become apparent that the tumor microenvironment, as well as other cells and factors accumulating in the host by virtue of tumor presence, plays a critical role in tumor growth and metastatic progression. The tumor-associated nonmalignant stroma consists of a wide variety of cells, including immune cells, whose function is modified by the interaction with the growing tumor to generate a favorable microenvironment and tumor-supportive general setting in the host. Intriguingly, on many occasions, these nonmalignant cells play a role that is strikingly different than they do under noncancerous conditions and actively act against the host to promote tumor growth and metastatic progression. Concerning possible plasticity and polarization in cancer, most studies to date are focused on plasticity and epithelial to mesen- chymal transition (EMT) of cancer cells with little emphasis on plasticity of stromal or tumor-infiltrating cells. One example of stromal plasticity that was described almost two decades ago and is widely recognized is that of the endothelial cells. Shortly after tumor initiation these cells change their phenotype as part of the "angiogenic switch" that is crucial for further tumor development (1). The angiogenic switch is a discrete step in tumor development occurring at different stages of tumor progression, depending on the nature of the tumor itself and its microenvironment. This initiation of angiogenesis has to occur to ensure further growth of the tumor (1). Following our recent work further elucidating and demonstrating functional plasticity in neutrophils (2), we will discuss these cells whose function is altered by the presence of a tumor and highlight the contribution of the alternatively activated cells. We will expand on this plasticity in immune cells with special emphasis on tumor-associated neutrophils (TAN), delib- erate shortly on it in nonimmune cells, and suggest a new parallel motive in cancer development, the "immunosuppressive switch." Plasticity in Immune Cells—"the Immunosuppressive Switch" The immune system, in principle, acts to protect the host against a wide variety of threats, including not only exogenous threats such as microbial infections but also against the propa- gation of naturally occurring aberrant host cells. However, in the context of cancer, immune cells undergo a dramatic phenotypic change and are regarded as "alternatively activated." Instead of protecting the host, the "alternatively activated" immune cells act to promote tumor growth and progression. Here, we will high- light the roles played by immune cells that exhibit functional plasticity, which allows the switch toward a tumor-supporting phenotype. We believe that in fashion similar to the angiogenic switch, these changes get to a critical turning point, conferring an immunosuppressive environment. Neutrophils Neutrophils provide the first line of defense against microbial infections and take a pivotal role in inflammation. Their role in cancer, however, has long been a matter of controversy. As early as the 1970s, neutrophils were shown to be capable of efficiently killing tumor cells. Since then, a plethora of studies have 1 Department of Developmental Biology and Cancer Research, Insti- tute for Medical Research Israel Canada, Hebrew University Medical School, Jerusalem, Israel. 2 Institute of Pulmonary Medicine, Hadassah- Hebrew University Medical Center, Jerusalem, Israel. Corresponding Authors: Z. Granot, Institute for Medical Research Israel- Canada and Hebrew University-Hadassah Medical School, Ein Kerem, Jer- usalem 91120, Israel. Phone: 972-2-6758337; Fax: 972-2-6757482; E-mail: zvikag@ekmd.huji.ac.il; and Z.G. Fridlender, Institute of Pulmonary Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. E-mail: fridlender@hadassah.org.il doi: 10.1158/0008-5472.CAN-15-1502 Ó2015 American Association for Cancer Research. 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