Identification of novel liquid biopsy biomarker for monitoring the immune set point in both solid tumor and hematological malignancy patients.

Abstract

52 Background: We identified an extracellular pathway that plays a role in modulating T cell activity in vivo, which we call the Resokine Pathway. The pathway specifically involves a 60 amino acid domain of the tRNA Synthetase for Histidine, which is an essential gene in all cells, including tumor cells, vis-a-vis protein synthesis. Methods: Circulating Resokine levels were measured in 466 plasma samples from patients bearing a number of different tumor types, as well as healthy individuals, using an ECLIA format with sensitivity to 5pM. Serum Resokine levels were also measured in tumor-bearing mice. Results: Low, Circulating Resokine Levels in Cancer Patients are Negligible Compared to Healthy Individuals: Resokine levels in healthy volunteers (n = 148) ranged from 8pM - > 2333pM with 18% of the individuals possessing a level below 30pM. In contrast, levels measured across patients with all tumor types tested ranged from 20pM to > 2333pM (above the upper limit of quantification) with only 4% of the patients possessing low levels, defined as < 30pM; (P < 0.0001). Tumors in Mice Induce Higher Circulating Resokine Levels: Resokine levels in serum from normal C57Bl6 mice ranged from 70 to 250pM (n = 10). Significantly higher levels (450-3000pM) were found in the serum of B16F10 tumor-bearing mice with up to a 10-fold increase in the mean serum level compared to healthy mice (p < 0.001). Resokine levels were correlated with tumor size. Conclusions: Resokine levels correlate with tumor size in mice, and are elevated in human cancer patients. This is consistent with the hypothesis that tumors secrete Resokine, to avoid detection by the immune system. Measurement of levels of the Resokine protein may offer a new liquid biopsy biomarker for tracking immune cell activity in cancer patients. It may also be a target for therapeutic intervention but the pathway may be challenging to inhibit given the presumably higher levels at the tumor and that there are many splice variants of HARS with potential activity (Lo et al. Science 2014, 345:328-32). Acknowledgements: We would like to thank Jedd Wolchok and Phil Wong of MSKCC, New York for access to patient samples.