Trends in Cancer
ReviewThe Untold Story of Granzymes in Oncoimmunology: Novel Opportunities with Old Acquaintances
Section snippets
The Changing View of GZMs in Cancer Immunity
The immune system has evolved a vast array of mechanisms to protect the host from pathogens and cancer while maintaining self-tolerance to prevent autoimmune reactions and other inflammatory disorders. Among these mechanisms, natural killer (NK) and cytotoxic T (Tc) cells (including αβ CD8+ T, γδ CD8+ T, and γδ CD8− T cells) recognize and kill pathogen-infected and cancer cells 1, 2. However, if uncontrolled, Tc and NK cells contribute to the pathology observed in inflammatory and autoimmune
GZMs As Immune Checkpoints
The cellular expression of GZMs is not restricted to Tc and NK cells, or to other populations involved in cancer immunosurveillance (Box 1 and Table 1). Other cells expressing GZMs, such as CD4+ T regulatory (Treg) lymphocytes, myeloid-derived suppressor cells (MDSCs), and dendritic cells (DCs), are involved in the homeostatic regulation of proinflammatory T cell activity [i.e., type 1 T helper cell (Th1), Th17, or Tc subsets], preventing autoimmune and inflammatory reactions. These types of
GZMs and Inflammation
GZMs are emerging also as key regulators of inflammation-related disorders (Box 2), and could thus contribute to cancer initiation and progression, as shown in inflammatory cancers [34]. Although several GZMs, including human and mouse GZMA, GZMM, GZMB, or GZMK, are able to modulate proinflammatory responses in different cell types (monocytes, macrophages, endothelial, epithelial, and fibroblast cells) in vitro 35, 36, 37, 38, 39, 40, 41, 42 and in vivo 31, 36, 43, 44, the available evidence
GZMs, ECM Remodeling, and Cancer Progression: A Time for Speculation
The ECM is a key component of the tumor microenvironment and a dynamic structure that regulates several steps of the tumor life cycle. ECM regulation of angiogenesis and receptor signaling are of special interest in cancer biology because they are involved in survival, proliferation, invasion, and metastasis.
The tumor microenvironment is rich in serine proteases that are usually produced by stromal and cancer cells, and which cleave ECM proteins that modulate angiogenesis and metastasis. Among
Other Roles of GZMs in Cancer Progression
Recent work has suggested a protumoral role of GZMM in EMT [66]. GZMM expression in human cancerous tissue correlates with cells expressing an EMT phenotype, and cancer cell lines in which GZMM was downregulated by shRNA induced less metastasis in mouse models. The mechanisms underlying this process are not clear. Although the authors suggested that GZMM activates STAT3 signaling, it is still not clear how this pathway could be activated in a culture of CRC lines where cytokines such as IL-6
GZMs As Therapeutic Targets in Cancer – Can Cytotoxic Effects Be Reduced?
The accumulated knowledge of immunoregulatory cell networks in cancer development and progression has allowed the development of more effective immunotherapies. We now know the key molecules to target to reduce chronic inflammation and thus prevent cancer onset and/or progression (i.e., UC-CRC or asbestos in mesothelioma) 3, 34, and more specific anti-inflammatory agents have been developed such as TNF-α or IL-6 blockers 68, 69. In addition, antibodies that block inhibitory immune checkpoints
Concluding Remarks
Accumulating evidence in mouse and human models suggests that GZMs are crucial regulators of many processes unrelated to cell death, such as inflammation, angiogenesis, ECM remodeling, and immune homeostasis. These novel functions of GZMs challenge the traditional dogma of a protective role of these proteases in cancer immunosurveillance and immunotherapy. Indeed, many processes regulated by GZMs are key promoters of cancer initiation and progression. The balance between antitumoral and
Acknowledgments
This work was supported in part by Fondo Social Europeo (J.P.) and Ministerio de Economia y Competitividad (SAF2011-25390) (J.P.) and SAF2014-54763-C2-1 (J.P.). L.S. and M.A. were supported by a grant from Fundación Santander/Universidad de Zaragoza and FPI/Ministerio de Economia y Competitividad (L.S.). P.J.S. was supported by a predoctoral contract from Gobierno de Aragon. J.P. was supported by Fundación Aragon I+D (ARAID). D.J.G. is funded by a Canadian Institutes for Health Research (CIHR)
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2021, International Journal of CardiologyCitation Excerpt :GZMK can serve as an accelerator of inflammatory processes that directly induce proinflammatory cytokine release, reactive oxygen species generation, endothelial dysfunction and subsequent immune cell recruitment [14,15]. As a secreted molecule, GZMK can also be found in the extracellular milieu where they will exert similar regulating functions [16,17]. In healthy individuals, serum GZMK levels were low or undetectable, whereas levels of soluble GZMK were notably elevated in the circulation under some inflammatory conditions [18–20].