Chemoradiation can induce ICD or tolerogenic cell death. ICD relies on the generation of damage-associated molecular patterns which can stimulate immune sensors such as toll-like receptors (TLRs). Activation of TLR pathways results in type-I interferon response that stimulates production of CXC-chemokine ligand 10 (CXCL10). We sought to determine whether we can predict clinical responses to chemoradiation and potential synergistic effect with immunotherapy by measuring surrogate biomarkers of ICD at baseline and after completion of chemoradiotherapy in cohort of locally advanced (LA) HNSCC treated with curative intent.
In a prospective cohort of 113 LA HNSCC pts we evaluated expression of TLR4, TLR7and TLR9 in the EpCAM+ circulating tumor cell (CTC) fraction at baseline and after cisplatin chemoradiation. We also quantified changes in chemokines CXCL10, CXCL16 and IL-2R.Data from The Cancer Genome Atlas (TCGA) was analyzed for association of aforementioned markers with overall survival (OS). Wilcoxon test was used to compare baseline with post treatment biomarker levels and Cox regression to assess their prognostic significance, with a two-sided p value < 0.05.
Upregulation of TLR9 was significantly associated with OS in TCGA provisional cohort (p = 0.04). In our cohort, 73 patients had evaluable specimens. Among cases with biomarker assessment at baseline and post treatment, 36.8% had an increase in CXCL10 levels with treatment (p = 0.022), 73.7% had an increase in CXCL16 levels (p = 0.002) and 63.8% had an increase in IL2Ra levels (p = 0.032). 52.0% of evaluable cases at baseline and post-treatment had an increase in TLR4 levels with treatment (p = 0.996), 42.9% had an increase in TLR7 levels (p = 0.042) and 27.7% had increase in TLR9 levels (p = 0.011). CXCL10 levels at baseline and post-treatment were significantly associated with OS (p = 0.032 and p = 0.018, respectively).
Our results suggest that chemoradiation leads to quantifiable effects in surrogate markers of ICD and these effects may inform trials combining chemoradiation with immune checkpoint inhibitors. In addition, CXCL10 has prognostic effect in pts treated with chemoradiation.
Clinical trial identification
Legal entity responsible for the study
Medical Ethical Committee of Attikon University Hospital.
Has not received any funding.
All authors have declared no conflicts of interest.