KEY TAKEAWAYS
- The study aimed to investigate the underlying mechanisms of ICI resistance in advanced melanoma by focusing on pts with dissociated responses.
- Researchers noticed comparable tumor T cell infiltration in intrapatient comparison of progressive vs regressive lesions, indicating no tumor immune exclusion.
Despite the success of immune checkpoint inhibition (ICI) in enhancing outcomes for advanced melanoma patients (pts), a subset experiences non-durable responses, prompting a crucial exploration of mechanisms underlying ICI resistance. J M Versluis and his team focused on the valuable subgroup with dissociated responses to uncover insights into treatment resistance.
Researchers performed an inclusive analysis by retrospectively screening Stage IV melanoma pts treated with ICI who exhibited dissociated responses. The study included 1 patient with metachronous regressive and progressive lesions at the same site, 2 pts with regressive and novel lesions at different sites, and 3 with regressive and progressive lesions at distinct sites. Additionally, 4 patients with acquired resistant tumor samples lacking a matched second sample were included.
In the majority of pts with dissociated responses in Stage IV melanoma undergoing ICI treatment, the progressive tumor lesions displayed higher CD8+/mm2 and interferon-gamma (IFNγ) signature levels. Notably, tumor PD-L1 expression levels remained similar between progressive and regressive lesions. Tumor mutational burden levels were higher in 2 out of 3 progressive lesions compared to their corresponding regressive tumors. Acquired tumor lesions exhibited elevated CD8+/mm2 counts and relatively high IFNγ signature levels. Genetic analysis revealed a stop-gaining mutation in the B2M and PTEN genes in 1 patient, while another showed a pathogenic POLE mutation.
The study concluded that intrapatient comparison of progressive versus regressive lesions revealed no defect in tumor T cell infiltration, and overall, no signs of tumor immune exclusion were observed.
Source: https://pubmed.ncbi.nlm.nih.gov/38280045/
Versluis JM, Hoefsmit EP, Shehwana H, et al (2024). “Tumor characteristics of dissociated response to immune checkpoint inhibition in advanced melanoma. Cancer Immunol Immunother. 2024 Jan 27;73(2):28. doi: 10.1007/s00262-023-03581-6. PMID: 38280045; PMCID: PMC10821835.
