Background: The impact of biologic aging on immune checkpoint inhibitor (ICI) toxicity and efficacy is underexplored in metastatic melanoma (MM). In peripheral blood T lymphocytes (PBTLs), biologic aging is characterized by changes in T-cell composition and cellular senescence. Whether indicators of PBTL biologic aging vary in MM patients or can be used to predict premature ICI discontinuation (pID) is unknown. Methods: We prospectively collected PBTLs from 117 cancer-free controls and 46 MM patients scheduled to begin pembrolizumab or nivolumab monotherapy. Seventy-four mRNAs indicative of T-cell subset, activation, costimulation/inhibition, and cellular senescence were measured by Nanostring. Relationships between each mRNA and chronologic age were assessed in patients and controls. Candidate biomarkers were identified by calculating the hazard ratio (HR) for pID in patients divided into low and high groups based on logtransformed mRNA levels or the magnitude by which each mRNA measurement deviated from the control trend (Δage). Area under the curve (AUC) analyses explored the ability of each biomarker to discriminate between patients with and without pID at 6 months and 1 year. Results: Fifteen mRNAs correlated with chronologic age in controls, including markers of T-cell subset, differentiation, cytokine production, and costimulation/inhibition. None of these mRNAs remained correlated with age in patients. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors comprising numerous subtypes whose metabolic profiles have yet to be fully examined. The present <em>in silico</em> study analyzed single-cell expression profiles from 2311 PitNET cells from various lineages and subtypes to elucidate differences in metabolic activities. Gonadotroph tumors exhibited high activities with histidine metabolism, whose activity is low in lactotroph tumors. Somatotroph tumors enriched for sulfur and tyrosine metabolism, while lactotroph tumors were enriched metabolism of nitrogen, ascorbate, and aldarate. PIT-1 lineage tumors exhibited high sulfur and thiamine metabolism. These results set precedence for further translational studies for subgroup/lineage specific targeted therapies.

9568 Background: Immune-checkpoint inhibitor (ICI) immunotherapy has increased survival in patients with melanoma. However, only half of the patients respond, and many experience immune-related adverse events (irAEs). Recent evidence suggests that modification of the gut microbiome may increase response to ICIs and decrease toxicity. Here we describe the first results of a clinical trial to determine if the microbiome can predict the response or toxicity during the first 16 weeks of ICI treatment. Methods: We enrolled patients aged 18 or older in a prospective observational cohort study at The Ohio State University Comprehensive Cancer Center Skin Cancer Clinic (OSUCCC-SCC) who were to receive treatment with pembrolizumab or nivolumab alone or in combination with other treatments (e.g. nivolumab and ipilimumab) for melanoma. Patients receiving systemic or oral corticosteroids at the start of ICI cycle 1 were excluded but were eligible if receiving adrenal physiologic replacement. Patients collected stool samples at baseline, within 2 days of an adverse event (if applicable), and at 12 weeks. The response to ICIs was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) at a 12-week computed tomography scan. Metagenomic whole-genome shotgun sequencing was performed on an Illumina NovaSeq 6000 and then classified using HUMAnN3. The effect of microbe relative abundances on potential irAEs was modeled by logistic regression with the R package glmm. Results: In total, 88 patients consented to the trial. Pre-treatment microbiome samples were collected from 49 patients. Potential irAEs were observed in 16 out of the 49 patients for whom pre-treatment microbiome samples were collected. There was no significant difference in the ages (p = 0.150, genders (p = 0.2), stages (p = 0.2) or treatments (p = 0.07) of those who developed potential irAEs. Pretreatment abundance of the family Ruminococaceae was most strongly associated with the development of a potential irAE (p = 0.03), followed by a taxon in an unclassified order within the phylum Firmicutes (p = 0.05). The family Bacteroidaceae was most strongly associated with no potential irAE (p = 0.05). Conclusions: Longitudinal and event-driven biospecimen collection in the context of treatment with immunotherapies was feasible in the OSUCCC-SCC. The abundance of the two high-taxonomic rank microbe groups was significantly associated with potential irAEs. The association with Ruminococaceae is consistent with previous studies where it was associated with response to ICIs and, in separate studies, development of an irAE was associated with a better response. The unclassified taxon is potentially a new biomarker for the prediction of toxicity and a therapeutic target to reduce treatment side effects. Future analyses will associate microbes with treatment response and test for consistent microbiome changes at the time of irAE development. Clinical trial information: NCT05102773.

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