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Soo Park, MD
Soo Park, MD
Posted: Thursday, December 5, 2024
Karol Prieto, PhD, of H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, and colleagues developed a novel Merkel cell carcinoma mouse model for investigating immunotherapy resistance. Their findings, which were presented during the 2024 Society for Immunotherapy of Cancer (SITC) Annual Meeting (Abstract 1363), may offer insight into the tumor microenvironment and potential therapeutic strategies.
“Resistance to immunotherapy remains a significant challenge, and the lack of targeted agents or highly effective strategies for recurrent or immunotherapy-refractory Merkel cell carcinoma further complicates the situation,” the investigators remarked. “Developing an appropriately credentialed immunocompetent animal model is crucial to tackle these issues.”
Tissue-based genomic testing of more than 148 ultraviolet radiation–driven Merkel cell carcinomas revealed enriched loss or mutation of RB1 and amplification of L-MYC. Guided by this information and the RPM model of small cell lung carcinoma (Rb1fl/fl; Trp53fl/fl; LSL-MycT58A/T58A), the investigators generated compound mutant mice (K14-CreERT2; Rb1fl/+; Trp53fl/+; LSL-MycT58A/+). Topical tamoxifen was applied to newborns, inducing the development of tumors that histologically resembled human Merkel cell carcinoma and expressed its markers (ie, CK20, CD56, and chromogranin A).
Based on RNA sequencing, the cells derived from the Merkel cell carcinoma mouse model clustered with human Merkel cell carcinoma samples but not with those of other skin cancers. Two cell lines from the K14-RPM-Cre model were injected into C57B/L6 mice; the 439-4120R cell line was found to fully respond to anti–PD-1 monotherapy, whereas the 438-856 cell line showed primary or acquired resistance. Fluorescence-activated cell sorting–based immunophenotyping of spontaneous mouse Merkel cell carcinoma tumors revealed a predominantly “cold” phenotype, the investigators noted.
“This model’s potential to guide novel immunotherapeutic interventions and strategies is promising, making it a crucial preclinical tool for advancing Merkel cell carcinoma treatment,” the investigators concluded.
Disclosure: No information regarding conflicts of interest was provided.
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