Figure 3. The mechanisms of enhanced Th17 cellular differentiation in cancer(+) patients after mRNA vaccination, facilitated by the SARS-CoV-2 spike protein. The induction of IL-6 and TNF-α, via the NF-κB response to spike, and the TGF-β induced expression of RORγt, enhances the generation of a Th17 population of cells that is responsible for the development of autoimmunity [166-169,172,173].
On top of this, the spike protein potentiates the signalling of the epidermal growth factor receptor (EGFR) [177]. Persistent activation of STAT3 is a common feature of the tumor microenvironment and a major contributor to the inflammatory state [178]. An intense activation of STAT3 can result from 1) an aberrant expression of IL-6 and subsequent stimulation of the IL-6 receptor [179], and 2) an intense activation of EGFR signalling as imposed by the spike protein [177]. These molecular events, illustrated in Figure 4, when they are happening concurrently, have the potential to bypass the inhibitory checkpoint of negative regulator suppressor of cytokine signalling 3 (SOCS3). SOCS3 would otherwise deactivate JAK in order to diminish STAT3 activation [179]. Moreover, the abnormally elevated expression of IL-6 and JAK/STAT3 signalling are pro-tumorigenic and enhance the differentiation of Th17 cells [179,180].