Back to Search Start Over

Close proximity of immune and tumor cells underlies response to BRAF/MEK-targeted therapies in metastatic melanoma patients

Authors :
Chi Yan
Sheau-Chiann Chen
Gregory Ayers
Caroline Nebhan
Joseph Roland
Vivian Weiss
Douglas Johnson
Ann Richmond
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

Subjects :
Immunology
Immunology and Allergy

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