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Close proximity of immune and tumor cells underlies response to BRAF/MEK-targeted therapies in metastatic melanoma patients
- Source :
- The Journal of Immunology. 208:118.03-118.03
- Publication Year :
- 2022
- Publisher :
- The American Association of Immunologists, 2022.
-
Abstract
- Acquired resistance to BRAF/MEK-targeted therapy occurs in the majority of melanoma patients that harbor BRAF-mutated tumors, leading to relapse or progression and the underlying mechanism is unclear in many cases. The tumoral spatial heterogeneity is a potential key to the understanding of the therapy-response relationships, but they also bring challenges of proper parameterization and model validation. In this study, we developed a workflow to detect immune and tumor cells using multiplex immunohistochemistry and spatial imaging analysis from whole-tumor imaging data. Simultaneous characterization of CD11c+, CD8+, CD40+, CD80+ and SOX10+ cells using multispectral imaging was performed on paired tumor sections from eleven melanoma patients prior to BRAF/MEK-targeted therapy and when disease progressed on therapy. We observed a significant increase of tumor cellularity in the progressed tumors, and the close association of SOX10+ melanoma cells with CD8+ cytotoxic T cells (Tc) negatively correlated with patient’s progression-free survival, which may indicate a potential mechanism for acquired resistance to BRAF/MEK-targeted therapy. Using preclinical mouse model of YUMM3.3 BRAF-mutated tumors, we showed the detrimental role of PD-L1:PD-1 axis between melanoma-cell:Tc-cell in melanoma. In TCGA-melanoma dataset (n=445), SOX10hi is associated with a significant reduction of IFNG and GZMB, as well as poor overall survival (OS) in melanoma. Tumor cellularity (SOX10 and MLANA expression) exhibited additive prognostic value in the immune score signature to predict OS in patients with early-stage melanoma and prognoses OS independent of immune score in patients with late-stage melanoma. This work was supported by a VA Merit Award (I01BX002301) and SRCS award to AR and by R01-CA116021 (AR).
- Subjects :
- Immunology
Immunology and Allergy
Subjects
Details
- ISSN :
- 15506606 and 00221767
- Volume :
- 208
- Database :
- OpenAIRE
- Journal :
- The Journal of Immunology
- Accession number :
- edsair.doi...........bd92da6bb17f7606a0f2f2151178deaa
- Full Text :
- https://doi.org/10.4049/jimmunol.208.supp.118.03