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Downregulation of CD109 on melanoma cells reduces ICI efficacy by inducing TIL resistance in melanoma cells during the effector phase

ABSTRACT: Although immune checkpoint inhibitors (ICIs) have improved the prognosis of melanoma, overcoming acquired resistance remains a challenge. The most critical mechanism is B2M mutation-mediated major histocompatibility complex (MHC) class I loss. Conversely, resistance mechanisms other than B2M mutations might be surmountable, although most of them are not yet fully understood. This study aimed to explore the novel mechanisms of acquired resistance in the absence of MHC class I loss. Previously, we established a pair of melanoma cell lines and cultured tumor-infiltrating lymphocytes (TILs) derived from an ICI-resistant melanoma patient with B2M mutation. Autologous TILs were unable to recognize the melanoma cells (MEL01), although genetic transduction of wild-type B2M (MEL01-B2M) reversed this phenomenon. To identify resistance mechanisms other than B2M mutation, we generated TIL-resistant MEL01-B2M cells by in vitro long-term co-culture (MEL01-B2M-R) and compared gene expression profiles between MEL01-B2M and MEL01-B2M-R. CD109 expression in MEL01-B2M-R cells was reduced by < 20%. Although CD109 has attracted attention as a negative regulator of transforming growth factor beta in allergic diseases, its effect on TILs, which play a central role in the efficacy of ICIs, remains unknown. Immunohistochemical analysis of 142 patients with melanoma revealed that low CD109 expression was associated with poor prognosis, regardless of MHC class I retention in melanoma tissues. In the co-culture assay, the knockout of CD109 in melanoma cells significantly impaired recognition and killing by specific TILs. These findings suggest that CD109 may serve as a predictive biomarker of ICI efficacy and as a novel therapeutic target for overcoming ICI resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309150 | GEO | 2025/09/30

REPOSITORIES: GEO

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Project description:Although immune checkpoint blockade (CPB) leads to prolonged responses in 15-40% of patients with metastatic melanoma, treatment refractory disease and progression after initial response remain major causes of mortality. While predictors of response have been reported, the common mechanisms of both primary and acquired resistance are poorly understood. To identify mechanisms of resistance and examine the evolving landscape in response to CPB, we performed whole exome sequencing (WES), immunohistochemistry (IHC), and RNA-sequencing (RNAseq) of longitudinal tumor biopsies from 17 metastatic melanoma patients treated with various CPB therapies. We found no significant changes in both mutational and neoantigen loads over time between responders and nonresponders. However, we identified abnormalities in one gene, beta-2-microglobulin (B2M), an essential component of MHC Class I antigen presentation, that were present in samples during disease progression but not regression. In total, we identified B2M aberrations in 29.4% of patients, including multiple early frameshift mutations, loss of heterozygosity (LOH) overlapping B2M, and absence of tumor-specific B2M protein expression. Additional defects in the antigen presentation and IFNγ pathways were identified but were not restricted to progressing lesions in our cohort. In two independent cohorts of 105 and 38 melanoma patients treated with ipilimumab (anti-CTLA4) and pembrolizumab (anti-PD1) respectively, we found that B2M LOH was enriched 3-fold in nonresponders (~30%) vs. responders (~10%) and associated with poorer overall survival (log-rank p=0.01, p=0.006). Loss of both copies of B2M was found only in nonresponders. We also found evidence for association of LOH overlapping IFNGR1 with poorer overall survival exclusively in the anti-PD1 cohort. Thus, B2M loss is likely a common mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1.

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Downregulation of CD109 on melanoma cells reduces ICI efficacy by inducing TIL resistance in melanoma cells during the effector phase

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