Abstract A006: LINC00261 acts as a surrogate biomarker for tumor DNA mutational burden and immunotherapeutic response in lung adenocarcinoma

Abstract

Defects in DNA repair allow for the age-dependent accumulation of mutations, which is significantly linked to the age-dependent increase in the development of neoplasia. Our lab has identified the long non-coding RNA LINC00261 as a critical activator of DNA damage signaling whose expression increases with age in normal lung tissue but is lost in the majority of Lung Adenocarcinomas (LUAD). We therefore undertook a mechanistic investigation on the relationship between LINC00261 function in lung and the accumulation of mutations by utilizing expression and mutational load data from The Cancer Genome Atlas, as well as in vitro mechanistic investigation into the functional relationship between LINC00261 and tumor mutational burden (TMB). Here we report (1) the observation of an age-dependent increase in LINC00261 expression in normal lung tissue within the TCGA adjacent non-tumor lung dataset; (2) a significant correlation between TMB and LINC00261 expression, where elevated LINC00261 levels are associated with decreased TMB; (3) LINC00261 effects on TMB were driven primarily by transition mutations, characteristic of defects in nucleotide excision repair. Standard of care treatment for disseminated LUAD often includes systemic platinum-based chemotherapies, including cisplatin, that act by inducing lethal levels of DNA damage. We observed that the presence of LINC00261 in LUAD causes cellular resistance to cisplatin-mediated DNA-damage in vitro. Our results suggest that patients with tumors expressing LINC00261 should be considered for non-platinum based therapeutic strategies. High mutational loads are also associated with the creation of neoantigens, allowing for immune recognition and when combined with PD-L1 expression levels can serve as an indicator for successful immunotherapy. Testing for PD-L1 expression is now standard of care, however exome sequencing to determine TMB is not often pursued outside academic medical centers due to expense, extensive bioinformatic involvement, and difficulty interpreting results. In addition, high levels of TMB does not always confer active neoantigen presentation as MHC Class II genes are often dysregulated in cancer. We therefore sought to determine if LINC00261 can function as a surrogate biomarker for TMB and provide complimentary indications to PD-L1 testing for successful immunotherapeutic response. Reintroduction of ectopic LINC00261 was able to activate expression of MHC Class II genes involved in neoantigen presentation. Conversely, Interferon gamma addition was able to induce endogenous expression of LINC00261 in vitro. Our results suggest there is a mechanistic relationship between LINC00261 expression and functional MHC Class II neoantigen presentation in LUAD. This was supported by observations that LINC00261 expression is significantly correlated to MHC Class II expression within TCGA LUAD cohort. Taken together, our results suggest LINC00261 shows promise as a biomarker of mutational burden and MHC Class II expression. Citation Format: Jonathan Castillo, Tianchun Xue, Mayela Norwood, Samantha Joseph, Crystal N. Marconett. LINC00261 acts as a surrogate biomarker for tumor DNA mutational burden and immunotherapeutic response in lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A006.