1256 Delineating the role of the microbiome and tumor microenvironment interactions driving mucosal melanoma response and resistance to immune checkpoint inhibitor treatment
Year: 2024
Type: conference-abstract
Abstract: Background Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology1 and low response rates to immune checkpoint inhibitors (ICIs).2 3 The biology of MM is poorly understood. We sought to prospectively, uniformly, and comprehensively profile a cohort of MM patients to determine the interplay of gut, mucosal and tumor microbiome on ICI response and resistance in advanced MM. Methods Patients with MM presenting to MD Anderson are prospectively enrolled for longitudinal collection for molecular, microbiome, and lifestyle factor profiling. Fecal microbiota was profiled by 16S ribosomal RNA gene sequencing (16S) and, in a subset of patients, whole metagenomic shotgun sequencing (WMS). Mucosal surface microbiota from tumor, tumor adjacent and buccal sites swabs was profiled by WMS. NanoString Digital Spatial Profiling (DSP) of formalin-fixed paraffin embedded (FFPE) MM tumor biopsies was performed to characterize the spatial tumor-immune interplay. Results 82 patients with sequenced fecal specimens and/or mucosal surface swabs have been enrolled. MM primary sites include 25 (30%) naso-oral, 30 (37%) anorectal, 14 (17%) urogenital, 10 (12%) conjunctival and 3 (4%) other. Subgroup analysis from 78 patients treated with ICIs displayed compositional differences between those fecal specimens collected at baseline/early on treatment (week 0 – 6, N = 43) compared to mid/late (from week 7, N = 35). Microbiome structure showed a distinct trend between responders (R) and non-responders (NR) at mid/late timepoint (p=0.09) but not at baseline/early. Differential abundance analysis showed higher abundance of Bifidobacterium and Collinsella in R at baseline/early and mid/late samples, respectively. Streptococcus was significantly enriched in R without ICI toxicity (beneficial group). Initial microbiome profiling and analysis of mucosal surface microbiome samples (n=42) revealed that microbial composition was driven by the MM primary site swabbed and not associated with response. DSP analysis from available tumor specimens (n=17) showed variable levels of immune infiltration with co-localization of the T-cell, lymphoid- and myeloid-cell markers. Conclusions This is an ongoing prospective study that is expected to drive insights into the tumor/microenvironment/host interactions to identify response and resistance biomarkers to ICIs in a rare melanoma subtype. Results from an initial analysis showed differences in the fecal microbiota in R and NR, and specific taxa, including taxa previously associated with favorable response to ICIs, were associated with response and toxicity. These results will be validated in a larger cohort. Future directions include interrogation of the tumor microbiome, molecular profiling, and germline predisposition, with the ultimate goal to improve treatment outcomes in MM. Acknowledgements This work was supported by the MD Anderson Patient Mosaic™ Project at The University of Texas MD Anderson Cancer Center. Patient Mosaic is supported by generous philanthropic contributions from the Albert and Margaret Alkek Foundation, among others. Trial Registration Not applicable. References Mihajlovic M, et al. Primary mucosal melanomas: a comprehensive review. Int J Clin Exp Pathol. 2012;5:739–753. D’Angelo SP, et al. Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis. J Clin Oncol. 2017;35:226–235. Dimitriou F, et al. Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study. Ann Oncol 2022 Sep;33(9):968–980. Ethics Approval The ability to contribute to this study was facilitated by an institutionally approved data use protocol with waiver of informed consent (2022–0428) approved by the MD Anderson institutional review board (IRB) (The MD Anderson IRB is registered with the Office for Human Research Protections (OHRP) under federal wide assurance number FWA00000363).
Authors: Florentia Dimitriou, Ashish V Damania, Priyadharsini Nagarajan, Sabitha Prabhakaran, Neus Bota, Randy Chu, Pranoti Sahasrabhojane, Yasmine Hoballah, Devarati Mitra, Roi Weiser, Shirley Y Su, Ehab Hanna, Bita Esmaeli, Travis T Sims, Curtis A Pettaway, Rodabe N Amaria, Isabella C Glitza, Jillian Losh, Nadim J Ajami, Scott Woodman, Jennifer A Wargo, Phillip Futreal, Jennifer McQuade
Institution: The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4404065563