Percutaneous cryoablation guided by imaging is a well-established, minimally invasive treatment for oncological conditions. We posited that cryoablation could alter the immune microenvironment by directly influencing the tumor, potentially eliciting an anti-tumor response in cases resistant to immune checkpoint inhibition (ICI). In this non-randomized phase II single-center study (<a href="https://www.clinicaltrials.gov/study/NCT03290677">NCT03290677</a>), individuals with unresectable melanoma experiencing progression on ICI underwent cryoablation in a single progressing metastasis, while ICI was continued for at least two additional cycles. The main objectives were to assess safety and feasibility and to evaluate tumor response in non-ablated lesions. Between May 2018 and July 2020, 17 patients participated in the study. The treatment regimen proved safe, revealing an objective response rate of 23.5% and a disease control rate of 41% (comprising 4 partial responses and 3 stable diseases). In our investigation into the factors influencing response to cryoablation therapy in ICI-resistant melanoma, we conducted single-cell RNA sequencing (scRNA-seq) using both 10x Genomics and Smart-seq2 technologies on biopsies from metastatic sites of 15 patients. We collected pre-treatment samples from all patients and post-treatment samples from 5 patients, totaling 20 samples. After quality control, excluding cells specific to anatomical sites or rare cell types (e.g., alveolar type II, neurons), and batch correction, we analyzed 49,071 single cells spanning melanocyte, endothelial, stromal, T, myeloid, and B/plasma cell lineages. Differential gene expression (DGE) analysis between myeloid cells identified the genes <a href="https://www.ncbi.nlm.nih.gov/gene/4082">MARCKS</a> and <a href="https://www.ncbi.nlm.nih.gov/gene/3586">IL10</a>, two genes involved in anti-inflammatory responses that can inhibit macrophages activation to be associated with failed response. Moreover, DGE analysis of T cells identified the gene <a href="https://www.ncbi.nlm.nih.gov/gene/7294">TXK</a>, which acts as a Th1 transcription factor, and the gene <a href="https://www.ncbi.nlm.nih.gov/gene/1240">CMKLR1</a> (chemerin-like-receptor-1), which triggers migration of CD8 T-cells to be upregulated in patients who benefited from cryoablation treatment. In contrast, <a href="https://www.ncbi.nlm.nih.gov/gene/10797">MTHFD2</a> and <a href="https://www.ncbi.nlm.nih.gov/gene/8836">GGH</a>, two genes involved in one-carbon metabolism and the folate cycle, were upregulated in T cells from patients who did not respond to therapy. Our analysis revealed a significant increase in B/plasma cells in patients who responded positively to the therapy combination, along with an enrichment of oxidative phosphorylation in T cells among non-responsive patients with progressive disease. These findings advocate for further investigation into this innovative and synergistic therapeutic approach.

Phase II Study of Cryoablation and Post-Progression Immune Checkpoint Inhibition in Metastatic Melanoma

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