Abstract SY06-01: Tumor-associated myelomonocytic cells as therapeutic targets

Abstract Since Rudolf Virchow’s discovery in 1863 of the link between inflammation and cancer, our knowledge about the physiopathologic processes underlying cancer-related inflammation has steadily increased (1). In their seminal paper in 2000, Hanahan and Weinberg proposed that most—if not all—human cancers have acquired six functional capabilities during their development: self-sufficiency in growth signals, insensitivity to antigrowth signals, tissue invasion and metastasis, limitless replicative potential, sustained angiogenesis, and evading apoptosis (2). This engagingly simple scheme has dictated the cancer research scenario over the past decade. Consequent to the intense experimental work devoted to the cellular and molecular mechanisms underlying carcinogenesis and tumor progression in the twenty-first century, Hanahan and Weinberg added four other capabilities to the scheme: altered metabolism, genetic instability, escape from immunosurveillance, and chronic inflammation (3]) This new point of view emphasized the striking concept that tumors should no longer be viewed as cell-intrinsic genetic diseases. Indeed, it is recognized that cancers arise, progress, and respond to therapy from within a complex microenvironment with which they continuously interact. The tumor microenvironment (TME) is a complex network, which includes soluble factors and components of the extracellular matrix as well as stromal, endothelial, and immune cells. Immune cells and, among them, myeloid cells play important roles in cancer development and can promote or inhibit cancer initiation and progression (4). Among tumor-infiltrating immune cells, macrophages are well-known determinants of cancer-related inflammation and are typically characterized by their remarkable plasticity. This consists of the ability to acquire a wide spectrum of activation states in response to various signals derived from the microenvironment. Classical M1 and alternative M2 macrophages represent the paradigm of this property. Tumor-associated macrophages (TAMs) usually display a so-called “M2-like” phenotype that can foster tumor progression in different ways, namely by promoting genetic instability, angiogenesis, and metastasis and by restraining antitumor adaptive immunity. Notably, TAMs can also play a dual role in the response to conventional antitumor therapies: they can enhance the antineoplastic effect or, in contrast, they can sustain a tumor-promoting response and so foil the anticancer power of these drugs (5). Given their roles in tumor development, a number of macrophage-targeted anticancer approaches are currently being evaluated. They include inhibition of macrophage recruitment and/or survival at tumor sites, functional reprogramming of TAMs to the antitumor M1-like phenotype, and enhancement of killing and/or phagocytosis of cancer cells. Moreover, TAMs express checkpoint proteins that modulate T-cell activation in such a way that they can be targeted by checkpoint-blockade immunotherapies. Also, neutrophils can affect the TME. However, unlike macrophages, they do so by releasing stored and newly synthesized inflammatory mediators. In the “classic,” albeit now obsolete, point of view, neutrophils were viewed as terminally differentiated effector cells that play major roles in the acute inflammatory response and antimicrobial defense. This limited standpoint was challenged by the finding that neutrophils can infiltrate tumors, interact with a number of cell populations, and produce a wide array of cytokines and effector molecules that exert a plethora of effects on tumor behavior (6, 7). Therefore, macrophages and neutrophils are both involved in the regulation of the innate and adaptive immune responses in various inflammatory situations, including cancer. Besides immune cells, innate immunity comprises a humoral arm that includes a variety of molecules, namely complement components, collectins, ficolins, and pentraxins. The role of the humoral arm of the innate immune system in cancer-related inflammation is still being evaluated. PTX3 deficiency was recently found to increase susceptibility to mesenchymal and epithelial carcinogenesis in mice (8). In detail, tumor-infiltrating leukocytes and endothelial cells were found to be a major source of PTX3 and to contribute to PTX3-mediated protection against carcinogenesis. PTX3 deficiency was associated with enhanced macrophage infiltration, proinflammatory cytokine production, angiogenesis, complement C3 deposition, and C5a levels, which suggests exacerbated cancer-related inflammation. Moreover, genetic inactivation of C3 reverted the increased susceptibility to 3-MCA-induced carcinogenesis and macrophage recruitment. PTX3 regulated C3 deposition on sarcoma cells by recruiting the negative complement regulator factor H. In addition, CCL2 inhibition was sufficient to revert the increased susceptibility of PTX3-deficient mice to carcinogenesis and the M2-like phenotype of TAMs. Thus, in 3-MCA sarcomas, unleashed complement activation and increased C5a production associated with PTX3 deficiency is likely to increase the production of CCL2, which in turn recruits tumor-promoting macrophages and favors M2-like polarization. PTX3 deficiency was also associated with increased DNA damage, which is in accordance with the theory that cancer-related inflammation contributes to the genetic instability of tumors. Moreover, the PTX3 gene was found to be highly methylated in some human mesenchymal and epithelial tumors, and these epigenetic modifications were responsible for silencing of PTX3 protein. Thus, an essential component of the humoral arm of innate immunity and regulator of complement activation works as an extrinsic oncosuppressor gene in mice and humans by modulating complement-mediated, macrophage-enhanced, tumor-promoting inflammation [8]. In an increasingly more personalized treatment approach, the more accurate understanding of cancer-related inflammation has led to new therapeutic options that target the TME. These strategies include inhibition of inflammatory mediators or of their downstream signaling molecules, blockage of recruitment/activation of myeloid cells, modulation of their immunosuppressive properties, and re-education of TME. These novel therapeutic strategies could synergize with conventional anticancer treatment and so significantly improve the patient’s clinical outcome and follow-up. Citation Format: Maria R. Galdiero, Martina Molgora, Cecila Garlanda, Gianni Marone, Alberto Mantovani. Tumor-associated myelomonocytic cells as therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY06-01. doi:10.1158/1538-7445.AM2017-SY06-01