Abstract A53: Phosphorylation of eIF4E promotes phenotype switching and MDSC-mediated immunosuppression in melanoma
Authors: Huang Fan , Gonçalves Christophe , Guo Qianyu , Rémy-Sarrazin Joelle , Emond Audrey , Yang William , Plourde Dany , Bartish Margarita , Su Jie , Zhan Yao , Gimeno Marina G. , Khoury Elie , Benoit Alexandre , Dankort David , Miller Wilson H. , del Rincón Sonia V. 
Published: March 2020

Introduction: Melanoma is the deadliest form of skin cancer. Melanoma phenotype switching is characterized by reduced expression of melanocyte lineage transcription factor MITF and its downstream targets, leading to increased invasiveness of melanoma cells and resistance to both targeted therapy and immunotherapy, and worse prognosis. In melanoma, MAPK and PI3K pathways ultimately converge upon eukaryotic translation initiation factor 4E (eIF4E) to induce its phosphorylation (p-eIF4E), which is critical for the oncogenicity of eIF4E. Here, we investigate the role of p-eIF4E in melanoma progression and tumor immunity.

Methods: We crossed p-eIF4E deficient (eIF4EKI) mice with an inducible melanoma mouse model. We monitored the primary tumor outgrowth, metastasis, and survival of the eIF4EKI mice versus eIF4EWT mice. Melanoma samples were isolated for further investigation.

Results: Compared to the eIF4EWT mice, eIF4EKI mice exhibit significantly delayed tumor growth, reduced metastasis, and increased survival. Increased expression of MITF and downstream melanoma antigens were observed in eIF4EKI tumors, suggesting a p-eIF4E-mediated phenotype switching. Cytokine array analysis revealed a novel proinvasive cytokine signature in eIF4EWT melanoma primary culture, further supporting a role of phospho-eIF4E in phenotype switching. The cytokine profiling also revealed a pro-myeloid-derived suppressor cell (MDSC) cytokine signature in the eIF4EWT tumor, indicating a p-eIF4E-linked immunosuppression. In support of the immune suppressive cytokine signature associated with phospho-eIF4E expressing melanomas, immune phenotyping of eIF4EWT melanomas showed a significant increase in MDSCs and less cytotoxic T cells, compared to eIF4EKI melanomas. Finally, pharmacologic inhibition of p-eIF4E in combination with anti-PD-1 immunotherapy results in a synergistic delay in primary tumor outgrowth and reduced metastasis.

Conclusions: Here we showed that phosphorylation of eIF4E promotes melanoma phenotype switching, leading to increased invasiveness and reduced expression of tumor-associated antigens. Further, by increasing the secretion of pro-MDSC cytokines, p-eIF4E permits an immunosuppressive microenvironment. Pharmacologic inhibition of p-eIF4E sensitizes melanoma to anti-PD-1 immunotherapy, potentially by increasing melanoma antigen expression and compromising MDSC-mediated immunosuppression. This study provides a novel therapeutic approach for the treatment of melanoma.

Citation Format: Fan Huang, Christophe Gonçalves, Qianyu Guo, Joelle Rémy-Sarrazin, Audrey Emond, William Yang, Dany Plourde, Margarita Bartish, Jie Su, Yao Zhan, Marina G. Gimeno, Elie Khoury, Alexandre Benoit, David Dankort, Wilson H. Miller, Sonia V. del Rincón. Phosphorylation of eIF4E promotes phenotype switching and MDSC-mediated immunosuppression in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A53.