1277 Unique microbial signatures are associated with clinical outcomes of metastatic melanoma after immune checkpoint blockade (ICI) therapy

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Background

There has been mounting evidence supporting the importance of the tumor microenvironment (TME) in oncogenesis¹ and treatment outcomes² in many malignancies. In the era of immuno-oncologic agents and multimodal therapy for metastatic melanoma,^{3 4} the TME has immense relevance in guiding systemic and local treatment options. In this study, the TME of patients status-post metastasectomy following ICI were investigated and associations with ICI response, site of metastasis, and survival outcomes were tested.

Methods

Tumor formalin-fixed paraffin-embedded (FFPE) samples from patients with metastatic melanoma were put through MSK-IMPACT,⁵ a targeted DNA sequencing platform that enables robust identification of tumorigenic mutations in over 500 genes from specific regions of interest in the human genome. A proportion of these reads were off-target and were isolated and searched for sequence homology with the NCBI nucleotide database,⁶ identifying microbial (bacteria and fungi) genera in the sequenced tissue. The output was cross-referenced with a list of known contaminants to exclude from analysis. An internally developed R script was then used to quantify the reads for each genus, after which odds ratios to elucidate microbial enrichments between subgroups were calculated and statistical difference was determined using chi-squared analyses.

Results

The patient group (n=160) had a median age of 61 (IQR 51, 69) and was predominantly male (60%). Mean (median) follow-up was 29 (19) months. ICI regimens given were combination anti-CTLA4/anti-PD1 (46%), anti-PD1 (38%) and anti-CTLA4 (16%). Multifocal progressors on ICI (n=70; 44%) showed significant enrichment of cutibacterium (73% vs. 51%; OR 2.62; p = 0.016) compared to those with partial/significant response. Patients with a higher severity metastatic site like the liver, viscera, bone, and CNS (n=75; 47%) were found to have significantly enriched levels of cutibacterium (79% vs. 45%; OR 4.55; p < 0.001), malassezia (42% vs. 25%; OR 2.30; p = 0.035), and actinomyces (14% vs. 3%; OR 5.25; p = 0.041) compared to those with lower severity metastases (skin, soft tissue, lymph nodes). Finally, patients who died of disease in less than 24 months (n=45; 28%) showed enrichment of bordetella (21% vs. 8%; OR 3.11; p = 0.050) compared to those with more durable survival.

Conclusions

These findings highlight potential biomarkers in the TME, suggesting several directions for future studies to leverage large-scale genomic sequencing to identify microbial signatures that can form the basis of prognostication and targeted therapeutics.

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