Abstract 6090: Integration of innate and adaptive immune signatures for early detection of cancer

Abstract Up to 50% of cancer patients are diagnosed at a late stage with tumors that are often unresectable, leading to intensive treatments and a preventable loss of life. Whilst multiple assays have been developed to tackle the issue of disease mortality, these approaches have serious limitations. For example, circulating tumor DNA (ctDNA) preferentially detects hard-to-treat tumors and micrometastatic disease, with limited sensitivity and specificity for early-stage malignancy, underscoring an urgent need for novel early detection strategies. Substantial evidence exists to demonstrate that signals related to innate (e.g. pro-inflammatory cytokines) and adaptive (e.g. antibodies and T cell receptors [TCRs]) immune engagement arise early in the development of cancer. The immune system therefore offers potential as an exquisitely sensitive and highly specific intrinsic early detection system for cancer. Here we propose the development of a pan-cancer novel early detection assay, using peripheral blood to measure three key cancer-specific components of the anti-tumor immune response: i) T cell receptor (TCR) sequences, ii) antibody signatures, iii) cytokine markers. Our preliminary data demonstrates that an age and smoking-matched cohort of lung cancer patients can be distinguished from healthy donors using TCR sequencing data processed through a published machine learning approach (p<0.01). In support of this, a pilot study on a custom peptide microarray comprised of lung cancer associated antigens and recurrent neoantigens demonstrated that lung cancer patient samples show significantly higher antibody intensities than healthy donors. Thirdly, using data from a prospective cohort study, we have demonstrated that inflammatory markers can be leveraged to predict future cancer diagnosis, and identified key protein markers for future work. These data provide proof-of-principle for the use of these analytes as a tool for early detection. We are actively curating a unique cohort of samples for this work from a prospective study, Nodule Immunophenotyping Biomarker for Lung Cancer Early Diagnosis (NIMBLE) (NCT05432739), which recruits patients with indeterminate lung nodules that may represent early cancers (>280 patients to date). This malignancy has high mortality rates and a significant need for early detection strategies. Through this, we aim to understand the early immunobiological response to cancer and leverage this information to design a novel multi-parametric immunopredictor assay for early detection of cancer. Citation Format: Evelyn Fitzsimons, Alexander Coulton, Hongchang Fu, Marcellus Augustine, Richard Lee, James Reading, Kevin Litchfield. Integration of innate and adaptive immune signatures for early detection of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6090.