The Spike Protein, Macrophages and Smoldering Inflammation: Yet Another Driver of Turbocancers

The Spike Protein’s polarizing effect on Macrophages may help explain the sudden rise in turbocancer diagnoses as it appears to be gasoline on the fire.

Tumor-associated macrophages favor tumor development through different functions. TAMs have various roles in tumorigenesis and as such, interact closely with cancer cells and the TME. TAMs create a pro-tumoral immune environment by: inactivating cytotoxic T cells through PD-L1 expression; and producing various cytokines to recruit regulatory T cells (IL-6, IL-10 and TGF-ß) and create an inflammatory milieu (IL-6, IL- 1ß, CXCL8). TAMs shape the extracellular matrix by producing proteases such as matrix metalloproteinases or cathepsins that degrade collagen fibers and ensure their turnover. TAMs also produce cross-linking enzymes that modulate the stiffness of the extracellular matrix. TAM-secreted VEGF promotes angiogenesis that facilitates tumor progression as well as metastasis. TAMs migrate with cancer cells to blood vessel where they create openings known as “TMEM doorways”, allowing cancer cells to disseminate in the circulation. Finally, TAMs produce TGF-ß and CCL18 that have a role in epithelia to mesenchymal transition, allowing cancer cells to migrate. Mesenchymal cells promote TAM activation through GM-CSF production.

The Spike Protein has been associated with a very cryptic and sinister symptom of PASC. That is the presence of low-level cytokines, causing an almost imperceptible level of chronic inflammation.

In this cross-sectional study, blood samples were obtained from three different sites in Australia from individuals with i) a resolved SARS-CoV-2 infection (and no persistent symptoms i.e. ‘Recovered’), ii) individuals with prolonged PASC-CVS and iii) SARS-CoV-2 negative individuals. Individuals with PASC-CVS, relative to Recovered individuals, had a blood transcriptomic signature associated with inflammation. This was accompanied by elevated levels of pro-inflammatory cytokines (IL-12, IL-1β, MCP-1 and IL-6) at approximately 18 months post-infection. These cytokines were present in trace amounts, such that they could only be detected with the use of novel nanotechnology. Importantly, these trace-level cytokines had a direct effect on the functionality of pluripotent stem cell derived cardiomyocytes in vitro. This effect was not observed in the presence of dexamethasone. Plasma proteomics demonstrated further differences between PASC-CVS and Recovered patients at approximately 18 months post-infection including enrichment of complement and coagulation associated proteins in those with prolonged cardiovascular symptoms. Together, these data provide a new insight into the role of chronic inflammation in PASC-CVS and present nanotechnology as a possible novel diagnostic approach for the condition.

Cardiovascular symptoms of PASC are associated with trace-level cytokines that affect the function of human pluripotent stem cell derived cardiomyocytes
https://www.biorxiv.org/content/10.1101/2024.04.11.587623v1.full

Why is this important? Because it is this very low-level inflammation which can induce tumors. The Spike Protein’s interaction with macrophages almost certainly contributes to this type of inflammation. We notice a pervasive induction of low-level inflammation throughout the body - induced by the Spike Protein – and the additional presence of macrophages polarizing to the M1 phenotype. Please see my previous posts which document how the Spike Protein activates and polarizes macrophages.

The type of inflammation associated with increased cancer risk due to chronic infection or persistent irritation is often called “smoldering inflammation” (Mantovani and Sica, 2010). This nomenclature is used because the inflammation is low grade without overt clinical consequences. Activated macrophages are central to this type of immune response and work in concert with other immune cells (Balkwill et al., 2005). It has been hypothesized that these immune cells produce a mutagenic environment (Pang et al., 2007) by generating both reactive nitrogen and oxygen species. NO in particular reacts with peroxidates to give nitrosoperoxycarbonate and this reaction is a major driver of the chemistry of inflammation. This highly reactive compound and other products cause mutations in the adjacent epithelial cells (Meira et al., 2008; Pang et al., 2007). In addition, there is evidence that the inflammatory microenvironment also promotes genetic instability within the developing tumor epithelial cells (Colotta et al., 2009). In either case, the mutations are fixed after replication of the epithelial cells, a process that is stimulated by growth factors synthesized by the infiltrating or resident immune cells that include macrophages. These growth-promoting effects on tumors are caused by the production of IL-6 in hepatocellular carcinoma (HCC) (Lin and Karin, 2007; Naugler et al., 2007) and TNFα (Karin et al., 2006) and IL-6 in colitis associated cancers (Grivennikov et al., 2009).

Macrophage Diversity Enhances Tumor Progression and Metastasis
https://pmc.ncbi.nlm.nih.gov/articles/PMC4994190/

Indeed, the activated macrophage is associated with tumor initiation.

The macrophage phenotype associated with cancer initiation and promotion is comparable to the “activated” one (Gordon, 2003). However, once initiated and the tumors progress towards malignancy, the macrophage phenotype changes from the “inflammatory” type to one that resembles macrophages that promote tissue formation during development (Figure 1) (Pollard, 2004, 2009).

Macrophage Diversity Enhances Tumor Progression and Metastasis
https://pmc.ncbi.nlm.nih.gov/articles/PMC4994190/

Now, here is where it becomes really interesting. Readers may recall my discussions about the Spike Protein and its interactions with the Extracellular Matrix (ECM). Lo and behold, macrophages perform the same functions – most likely in tandem. Please note the following macrophage properties are tailor-made for developing a turbocancer. It is the proverbial “throwing gasoline on the fire.”

TAMs (Tumor Associated Macrophages) are also involved in active ECM remodeling, collaborating notably with cancer-associated fibroblasts (CAFs) to promote tumor cell intravasation [69]. Indeed, tumors often display a dense ECM that notably impairs drug penetration, limiting treatment efficacy and resulting in more metastases [70, 71].

Roles of macrophages in tumor development: a spatiotemporal perspective
https://www.nature.com/articles/s41423-023-01061-6

And now, unfortunately, for the grand finale. We can see with absolute clarity that SARS-CoV-2 is almost certainly an oncogenic virus par excellence. Enter the endothelium – and metastases.

EMT and ECM remodeling precede the intravasation of tumor cells into the circulation and their subsequent dissemination to distal organs. This key event in metastasis formation occurs at sites known as “tumor microenvironment metastasis (TMEM) doorways”, characterized by the dynamic association between one endothelial cell, one TAM and one cancer cell [80,81,82].

Roles of macrophages in tumor development: a spatiotemporal perspective
https://www.nature.com/articles/s41423-023-01061-6

The picture that forms is one of a two-pronged attack by the Spike Protein. It attacks the endothelium (to open lines, as we say in chess) and then “uses” our body’s own immune cells to destroy tissues and organs – and initiate chronic diseases. I will continue to work on understanding this pathogen and finding ways to combat it. Thank you, as always, for your readership, dialogue, and support.