Abstract C135: Notch as an immunologic basis of cancer disparity

Abstract

Abstract Identification of the host immune factors that influence naturally occurring lymphocyte responses is an important prerequisite to successfully design a successful immunotherapeutic modality. Lymphocytes, such as T-cells and NK cells differ significantly in their ability to mediate antitumor responses depending on the genetic and immunophenotypic constitution of the individuals. The major histocompatibility and the leukocyte receptor complexes are the two most polymorphic regions of the human immune genome. Individuals with increasingly diverse repertoires of MHC class-I molecules have a greater potential for their polyclonal T cells and natural killer (NK) cells to be responsive. Our work suggested that lymphocyte repertoire varies with host backgrounds and that tumor antigen-reactive activated CD8+T cells could enhance intratumoral NK cell function. Furthermore, our data indicate that by modulating the expression of hematopoietic and dendritic cell (DC) Notch ligands, tumors negatively direct lymphocyte differentiation away from their effector phenotype. In human lung tumor infiltrates, we noted a significant correlation between Notch ligand Jag1 or Jag2-expressing dendritic cells with the programmed cell death protein PD-1-expressing CD8+T-effector-memory cells (p = 0.0005). PD-1 expression in T-cells signifies their exhaustion, thus diminishing their survival and antitumor function. These differences in Notch components could underlie poor prognosis in African-Americans (AA). In the clinical trial NCT00774176, the expression of mastermind-like protein-1 that affects Notch-dependent angiogenesis correlated with COPD exacerbation in AA. Also, Notch2 N-terminal-like protein (N2N) was upregulated in various carcinomas as per the TCGA database, with increased N2N expression in AA relative to Caucasians (p = 0.0037). N2N represses the transcriptional activities of Notch2 and Notch1 intracellular domains, which we showed are important for antitumor T-cell function and memory. The comparative analysis of Caucasians and AA lung cancer patient tumor samples show appreciable ethnicity-specific differences in T-cell Notch parameters. Correspondingly, disparities in the expression of Notch components in ethnic minorities can affect antitumor lymphocyte immunity and impact cancer relapse. Citation Format: Anil Shanker, Pierre P Massion, David P Carbone, Mikhail M Dikov. Notch as an immunologic basis of cancer disparity [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C135.