1150P - Transforming growth factor-beta-1 and soluble co-inhibitory immune checkpoints as putative drivers of immune suppression in advanced basal cell carcinoma

Background

Basal cell carcinoma's (BCC) mortality rate is low; however, it is associated with substantial morbidity. Transforming growth factor-b1 (TGF-b1) is a key player in cell proliferation, differentiation, apoptosis, and immune regulation. TGF-b1 is associated with immunosuppression and resistance to immunotherapeutic drugs. The current study compared levels and possible associations between systemic soluble ICMs (sICMs) and a group of humoral modulators of immune suppressor cells in a cohort of patients with advanced BCC, (n=40) and a group of healthy control subjects (n=20).

Methods

We measured sICMs and immunosuppressive humoral modulators by using multiplex bead array or ELISA procedures. The sICMs comprised seven co-inhibitory (CTLA-4, BTLA, LAG-3, PD-1, PDL-1, PDL-2, and TIM-3) and eight co-stimulatory (CD27, CD28, CD40, CD80, CD86, GITR, GITRL, and ICOS) proteins, as well as the two dual-active sICPs, HVEM and TLR2. The 7 humoral modulators of immunosuppressor cells included arginase 1, fibroblast activation protein (FAP), RANTES (CCL5), interleukin-10, TGF-b1, and the M2-type macrophage biomarkers, soluble CD163 (sCD163) and sCD206.

Results

Plasma levels of six co-inhibitory sICPs, sCTLA-4, sLAG-3, sPD-1, sPD-L1, and 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 was significantly increased (p<0.0002) in the cohort of BCC patients, with the levels of the others essentially comparable with those of the control patients; of the dual active sICPs, sHVEM, sTLR2 was elevated (p<0.00001) and TLR2 comparable with the control group. Correlation heat maps revealed selective, strong associations of TGF-b1 with seven co-stimulatory (z=0.618468-0.768131) and 4 co-inhibitory (z=0.674040-0.808365) sICPs, as well as with sTLR2 (z=0.696431).

Conclusions

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-b1 in driving immunosuppression in this malignancy, possibly via activation of regulatory T cells.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

University of Pretoria and The Medical Oncology Centre of Rosebank.

Disclosure

All authors have declared no conflicts of interest.