Abstract PR004: Older adult-specific microbes correlate with treatment response and markers of T-cell senescence in NSCLC
Authors: Spakowicz Daniel , Hoyd Rebecca , Wheeler Caroline E. , Williams Nyelia , Bibi Amna , Husain Marium , Rajamouli Srichandhana , Suman Shankar , Amann Joseph , Grogan Madison , Vibhakar Pooja , Owen Dwight H. , Carbone David P. , Rosko Ashley , Burd Christin E. , Presley Carolyn J. 
Published: January 2023

Abstract
The gut microbiome changes with age and affects many aspects of human health, including response to cancer treatments. Cancer survival rates have improved with new treatment options, including immune checkpoint blockade (ICB); however, the objective response rate remains low. Manipulation of the microbiome is a promising approach to improving cancer outcomes, but the effect of age is understudied. Here, we sought to understand whether (1) specific microbes are associated with treatment response in older adults with non-small cell lung cancer (NSCLC) and (2) whether these microbes are the same as for younger adults. Next, we explored the causal effects of the microbiome on ICB response in mouse models and the relationship with blood-based markers of T-cell senescence. We conducted a prospective cohort study of adults ≥60 years with a new diagnosis of NSCLC who received any treatment modality. Stool was collected, and metagenomic whole-genome shotgun sequencing was performed. Blood T-cells were isolated, the RNA purified and then assessed for markers of senescence by nanostring. Response to treatment was determined by RECIST v1.1 criteria. Generalized linear regression was used to relate baseline microbiome abundances to treatment response and non-parametric correlations associated with CDKN2A (p16) expression to microbe abundances. To assess the causal role of the gut microbiome in ICB response, we gavaged gut microbiome samples from responders and non-responders into C57BL/6 mice to create human-microbiome avatar models. The mice were then injected with MC38 cancer cells and treated with anti-PD1 or isotype control antibodies, and tumor volume was measured over time. Biospecimens and best response data at three months were captured from 23 patients, of which five had a complete response, eight had a partial response, eight had stable disease, and two had progressive disease. Over 50 microbes were associated with a response after p-value adjustment. Responder stool was enriched for microbes associated with youth and ICB response (Bifidobacterium adolescentis, p = 2.64e-20). However, microbial taxa associated with response differed from those reported in younger populations (Firmicutes sp. CAG 145, p = 1.58e-20, Oscillibacter sp. 57-20, p = 7.96e-24). Stool from non-responders (NRs) was enriched in taxa previously linked to treatment-related toxicities and shorter progression-free survival (Streptococcus lutetiensis, p = 4.55E-24) but also contained microbes previously linked to response in younger adults (e.g., Roseburia sp. CAG 309, p = 5.16e-15). The T cell senescence marker, p16, correlated with the most enriched taxon in non-responders NRs (Streptococcus thermophilus, r = 0.45, p = 0.02), suggesting a connection between immune aging and the microbiome. Preliminary fecal transplant studies in mice showed improved ICB response in mice engrafted with stool from responders versus non-responders. Together, these data identify potential differences in the gut microbiomes of young and older adult NSCLC patients who respond to ICB.
Citation Format: Daniel Spakowicz, Rebecca Hoyd, Caroline E. Wheeler, Nyelia Williams, Amna Bibi, Marium Husain, Srichandhana Rajamouli, Shankar Suman, Joseph Amann, Madison Grogan, Pooja Vibhakar, Dwight H. Owen, David P. Carbone, Ashley Rosko, Christin E. Burd, Carolyn J. Presley. Older adult-specific microbes correlate with treatment response and markers of T-cell senescence in NSCLC [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 PR004.