Abstract 1764: Deciphering the role of TPC2 in cancer immunology: from bench to bedside

Abstract

Abstract Background: Ca2+ signals mediated by two-pore channels play roles in cancer, the mechanisms of the two-pore channel subtype 2 (TPC2) and its complex interplay between monocyte differentiation, the release of cytokines/chemokines and cancer remain elusive. Methods: We investigated TPC2's role in monocyte differentiation, macrophage development, and IL-8 and IL-10 production. In addition, we leveraged UK Biobank data to characterize the effects of 71 genetic variants within, but not limited to, TPC2, IL8, IL10 and TNF-α in cancer patients at a global level in terms of susceptibility, prognosis, disease recurrence and overall survival (OS). Out of 71 SNPs, 29 were in Hardy-Weinberg equilibrium (p-value > 0.05). Results: We identify a clear trend of increasing TPC2 expression at the RNA level during monocyte differentiation and macrophage development. We also observed an important link between TPC2 and the release of two mediators that are opposed in their functions: IL-8 and IL-10. A total of 322,341 subjects were reviewed: 265,547 cancer-free controls and 56,794 with a median age at cancer diagnosis of 59.90 (5.20–79.20). The results showed that carrying the TNF-α rs4645843 allele: TC was associated with a lower risk for developing cancer (OR: 0.81, 95% CI: 0.67–0.98,p-value = 0.031* vs. C/C), whereas carrying rs2069827:TG (IL-6), rs2255214:TG (ILDR1/CD86), rs375947:GA (IL12RB1), rs72932540:GA (close to TPCN2), and rs3024508:CA or rs3024508:CC (IL-10), was associated with an increased risk of cancer susceptibility ([OR: 1.03, 95% CI: 1–1.05, p-value = 0.042* vs. G/G], [OR: 1.025, 95% CI: 1–1.05, p-value = 0.029* vs. G/G], [OR: 1.02, 95% CI: 1–1.04, p-value = 0.035* vs. A/A], [OR: 1.06, 95% CI: 1.03–1.09, p-value = 2.76e-06 ***vs. A/A], [OR: 1.07, 95% CI: 1.02–1.12, p-value = 0.006** vs. A/A]) and [OR: 1.54, 95% CI: 1.03–2.32, p-value = 0.037* vs. A/A], respectively) after adjusting for sex and ethnicity. Genotypes CA in rs12720356 (TYK2) and CT in rs1799964 (TNF) showed lower incidence of metastatic cancer after adjusting for age, sex and ethnicity (OR: 0.65, 95% CI:0.43–0.97, p-value = 0.036 * vs. A/A)] and [OR: 0.5, 95% CI: 0.28–0.9, p-value = 0.022* vs. C/C], respectively). Genotype CC in rs12720356 showed lower rates of cancer recurrence after adjusting for age, sex and ethnicity (OR: 0.78, 95% CI: 0.63–0.97, p-value = 0.026* vs. A/A), whereas genotype AG/GG in rs11209026 showed higher odds of cancer recurrence after adjusting for age, sex and ethnicity (AG OR: 1.45, 95% CI: 1.03–2.04, p-value = 0.034* and GG OR: 1.41, 95% CI: 1.01–1.98, p-value = 0.046* vs. A/A). We found a significant difference in OS (N = 5202) in cancer patients who were carriers of genotype CA or CC in rs16858811 (CXCR1) and genotype TG or TT in rs2255214 (ILDR1/CD86) (p = 0.006 and p = 0.01, respectively). Conclusion: TPC2 profiling could enable the discovery of a novel cancer biomarker/hallmark and represent a further step towards personalized cancer immunotherapy. Citation Format: Abeer Alharbi, John Parrington. Deciphering the role of TPC2 in cancer immunology: from bench to bedside [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1764.