Cervical cancer remains a significant worldwide health challenge, with a high mortality rate for those cases diagnosed at an advanced stage that manifest associated leukocytosis. Hence, identifying clinically significant prognostic markers is critical, especially in these patients who demonstrate a need for the highest complexity in therapy and management.
2. Cancer-Related Inflammation
The year 2021 marked a decade since Hanahan and Weinberg published their landmark paper on the hallmarks of cancer; it identified “tumor-promoting inflammation” as a key enabling characteristic
[1]. In particular, the authors identified the inflammatory state of premalignant and malignant lesions—driven by cells of the immune system—as a strong promoter of tumor progression by different pathways. Rudolf Virchow, in 1863, was the first to link inflammation and cancer. He observed a high percentage of leukocytes infiltrating neoplastic tissue and hypothesized that the origin of malignancies could be consequent to chronic inflammation
[2]. Since then, pathologists have increasingly reported that various tumors are heavily infiltrated by both innate and adaptive immune cells, mimicking inflammatory conditions occurring in non-neoplastic lesions
[3];
rwe
searchers have recently demonstrated similar findings in a large and rapidly proliferating low abdominal lesion organized around the amniotic fluid that was composed predominantly of M1 macrophages, after a cesarean delivery
[4].
In the last years, scientific investigations on the connections between inflammation and cancer pathogenesis have grown, leading to conclusive proof of the significant tumor-promoting effects exerted by immune cells, mainly of the innate immune system
[5][,6][,7][,8]. Inflammation can promote cancer progression by providing bioactive molecules to the tumor microenvironment (TME), inclusive of growth factors, survival factors, proangiogenic proteins, extracellular-matrix-modifying enzymes that enable angiogenesis, invasion, and metastasis (
Figure 1). Moreover, during inflammation, innate immune cells can release, in addition to cytokines and chemokines, a large amount of reactive oxygen species as defense agents and products of hyperactivated energy metabolism (
Figure 1); these act on DNA and are mutagenic and promote oncogenesis
[6]. To date, inflammation and associated oxidative stress have also been known to concur with immune escape, with peculiar and reversible phenomena.
Figure 1. Epithelial cervical cancer microenvironment, tumor-associated inflammation, and paraneoplastic leukocytosis. The cervical cancer tumor microenvironment (TME) is composed of different cells, including epithelial cancer cells, fibroblasts, mesenchymal cells, and immune cells, i.e., macrophages, mast cells, dendritic cells, and neutrophils, as well as T and B lymphocytes. Cancer-related inflammation can promote cancer progression by providing bioactive molecules to the TME, inclusive of growth factors, survival factors, proangiogenic proteins (VEGF), extracellular-matrix-degrading enzymes (MMP-9) that enable angiogenesis, invasion, and metastasis. These signaling molecules are released by the immune inflammatory cells as well as by cancer cells themselves. Moreover, during inflammation, immune cells can release several cytokines and chemokines (IL-6, IL-1beta, TNF-alpha, IL-8, INF-gamma) as well as a large amount of ROS as defense agents and products of hyperactivated energy metabolism. In turn, cytokines engage innate immune cells, mainly macrophages and neutrophils, that finally promote tumor growth and immune-suppressive status favoring tumor escape. In this context, cervical cancer tumors may also tend to promote myelopoiesis and sustain an increase in leukocytosis. This event seems to be mediated by the production in the TME of specific cytokines as a G-CSF and IL-6, both by cancer cells and TME inflammatory infiltrate. Beside inducing myelopoiesis, these factors can also promote the assembling in TME of immature myeloid progenitors known as myeloid-derived suppressor cells (MDSCs), which are able to directly promote tumor progression, in particular angiogenesis, and also suppress cytotoxic T lymphocyte and natural killer (NK) cell activity, thus contributing to immune escape. Abbreviations: IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; ROS, reactive oxygen species; iNOS, inducible nitric oxide synthase; MMP, metalloproteinase; G-CSF, granulocyte-colony stimulating factor; VEGF, vascular endothelial growth factor. Created with BioRender.com.
Typically, immune responses may represent an effort by the immune system to eliminate tumors. However, this overactivity of the immune system may allow the tumor to evade the immune response. This peculiar condition is considered a paradoxical mechanism for immune escape by the tumor using surprisingly specific cells of the immune system known for their immunosuppressive activity. Thus, inflammation is present in some tumors during the earliest stages favoring tumorigenesis, and thereafter accompanying cancer during its evolution, until cancer-associated systemic symptoms are determined
[9].
The immune response against cancer can be divided into two phases. The initial phase is called “resistance”, where the body tries to get rid of cancer cells through the activation of the specific immune response. The tumor progression reflects the failure of the mechanisms of resistance as well as of the specific immunity; this is followed by a second phase of immune response, “the tolerance phase”, characterized by the prevalence of innate immunity consequent mainly to necrosis and the immunopathology phenomena. In this phase, the aspecific chronic inflammation sustained mainly by macrophages and neutrophils is prevalent. The persistence of these events negatively impacts immunosurveillance and determines severe systemic symptoms
[10].
To better understand these phenomena, it is fundamental to highlight that in establishing tumor-associated inflammation, the phenomena of cellular
necrosis are important. Necrosis related to cancer progression activates cells that release pro-inflammatory cytokines both in the TME and at the systemic level, as a physiological mechanism of repairing tissue damage, in the “tolerance phase”
[10]. Consequently, cytokines can, in turn, engage innate immune cells, mainly macrophages and neutrophils, whose roles in their antineoplastic activity remain unclear
[6][,11][,12]. Several studies have reported that the presence of aspecific immune cells in the TME, such as macrophages and neutrophils, can surprisingly promote tumor growth and orchestrate immune-suppressive status favoring tumor escape. Two types of tissue damage coexist (i) direct damage by the neoplasm and (ii) immunopathological damage. The latter, while seemingly beneficial in counteracting cancer growth, sustains the tumor escape and the cancer systemic symptoms through the associated production of dangerous chemokines and cytokines. As
reswe
archers have recently described, the cytokine storm during the evolution of cancer is the actual reaction responsible for these phenomena. Thus, most advanced cancers benefit from these phases of immune response that promote cancer progression instead of controlling its growth
[10][,13].
One of the most complex aspects to understand is the timing of the arrival and growth of specific immune cells within the neoplastic tissue that can affect the tumor immunophenotype itself
[1]. A tumor is not only an assembly of neoplastic cells, but also a heterogeneous growth of different specialized cells, such as fibroblasts, mesenchymal cells, macrophages, mast cells, and neutrophils, as well as T and B lymphocytes, that finally surprisingly concur with the growth of cancer itself. This sets the problem of explaining the tumor as a host or as an integral part of an organism that, however, has lost its physiological biological destiny. Consistently, several studies have revealed an expanding record of signaling factors secreted by inflammatory cells, which exert tumor-promoting activities (
Table 1). Conforming to the expression of these several mediators, tumor-infiltrating inflammatory cells have been reported to activate and aid in sustaining tumor angiogenesis, promote cancer cell proliferation, ease tissue invasion by being present in the peritumoral space, and favor the metastatic dissemination of cancer cells
[14][,15][,16][,17].
Table 1.
Definition of the main immune cells involved in cancer-related inflammation and paraneoplastic leukocytosis and their respective functions.
Category |
Cells |
Main Functions |
Cytokines/Effectors |
Myeloid |
Neutrophils |
Phagocytic cells that rapidly migrate to site of cancer/inflammation and recruit other immune cells Direct cytotoxicity Regulation of cytotoxic T lymphocytes response |
Proinflammatory cytokines (IL-6, IL-1b), ROS |
Tumor- associated macrophages |
Antigen-presentation and T cell activation in the first phase of antitumor immunity; Tumor-promoting activity with inhibition of T cell activity and proangiogenetic activity |
M1: IL-6,TNF-a, IL-1b, IL-6, IL-12, IL-23, iNOS, COX-2; M2: IL-10, VEGF, Arginase, MMP9, IL-8 |
Dendritic cells |
Antigen-presenting cells, that display antigen to activated T lymphocytes |
PDL-1 (immature dendritic cells) |
Myeloid derived suppressor cells |
Suppression of T cells and NK cells activity; Tumor promoting activity; Proangiogenetic activity |
ROS iNOS MMP9 Arginase |
Lymphoid |
T lymphocytes |
|
|
Cytotoxic T cells (CD8+) |
Direct lysis of cancer cells; production of cytotoxic cytokines |
|
T helper (CD4+) |
Help cytotoxic T lymphocytes (CTLs) in tumor rejection; B cell activation; production of cytokines |
INF-γ |
Treg cells (CD4+) |
Inhibition of CD8+ CTLs |
|
B cells |
Production of tumor-specific antibodies Activation of mast-cells |
Tumor-specific antibodies |
NK cells |
Direct cytotoxicity of cancer cells Production of cytotoxic cytokines |
INF-γ, VEGF |