Transforming growth factor-β1 and soluble co-inhibitory immune checkpoints as putative drivers of immune suppression in patients with basal cell carcinoma

Abstract

The current study compared the levels and possible associations between systemic soluble immune checkpoints (sICPs, n = 17) and a group of humoral modulators of immune suppressor cells ( n = 7) in a cohort of patients with basal cell carcinoma (BCC, n = 40) and a group of healthy control subjects ( n = 20).

The seven humoral modulators of immunosuppressor cells were represented by the enzymes, arginase 1 and fibroblast activation protein (FAP), the chemokine, RANTES (CCL5) and the cytokines, interleukin-10 and transforming growth factor-β1 (TGF-β1), as well as the M2-type macrophage markers, soluble CD163 (sCD163) and sCD206.

The plasma levels of six co-inhibitory sICPs, sCTLA-4, sLAG-3, sPD-1, sPD-L1, sTIM-3 and sPD-L2 were significantly elevated in the cohort of BCC patients ( p <0.001- p <0.00001), while that of sBTLA was significantly decreased ( p <0.006). Of the co-stimulatory sICPs, sCD27 and sGITR were significantly increased ( p< 0.0002 and p< 0.0538) in the cohort of BCC patients, while the others were essentially comparable with those of the control participants; of the dual active sICPs, sHVEM was significantly elevated ( p <0.00001) and TLR2 comparable with the control group. A correlation heat map revealed selective, strong associations of TGF-β1 with seven co-stimulatory ( z = 0.618468–0.768131) and four co-inhibitory ( z = 0.674040–0.808365) sICPs, as well as with sTLR2 ( z = 0.696431).

Notwithstanding the association of BCC with selective elevations in the levels of a large group of co-inhibitory sICPs, our novel findings also imply the probable involvement of TGF-β1 in driving immunosuppression in this malignancy, possibly via activation of regulatory T cells. Notab