The MNK1/2–eIF4E Axis Supports Immune Suppression and Metastasis in Postpartum Breast Cancer

Abstract

Breast cancer diagnosed within 10 years following childbirth is defined as postpartum breast cancer (PPBC) and is highly metastatic. Interactions between immune cells and other stromal cells within the involuting mammary gland are fundamental in facilitating an aggressive tumor phenotype. The MNK1/2-eIF4E axis promotes translation of pro-metastatic mRNAs in tumor cells, but its role in modulating the function of non-tumor cells in the PPBC microenvironment has not been explored. Here we used a combination of in vivo PPBC models and in vitro assays to study the effects of inactivation of the MNK1/2-eIF4E axis on the pro-tumor function of select cells of the TME. PPBC mice deficient for phospho-eIF4E (eIF4E S209A ) were protected against lung metastasis and exhibited differences in the tumor and lung immune microenvironment compared to wild-type mice. Moreover, expression of fibroblast-derived IL-33, an alarmin known to induce invasion, was repressed upon MNK1/2-eIF4E axis inhibition. Imaging mass cytometry on PPBC and non-PPBC patient samples indicated that human PPBC contains phospho-eIF4E high-expressing tumor cells and CD8 + T cells displaying markers of an activated dysfunctional phenotype. Finally, inhibition of MNK1/2 combined with anti-PD-1 therapy blocked lung metastasis of PPBC. These findings implicate the involvement of the MNK1/2-eIF4E axis during PPBC metastasis and suggest a promising immunomodulatory route to enhance the efficacy of immunotherapy by blocking phospho-eIF4E.

Multiplex Tissue Imaging: Spatial Revelations in the Tumor Microenvironment

“…The data table integrates single ion signals per pixel, after which image and single cell segmentation can be converted to single-cell data for downstream analysis. In cancer research, IMC is used to discover novel phenotypes and biomarkers, or to study TME heterogeneity [22][23][24][25][30][31][32]36,43,44,50]. IMC is also used to predict prognosis and therapy responses in humans or in mice [23,30,51,[65][66][67][68][73][74][75].…”

Identification of Tumor Microenvironment-Related Prognostic lncRNAs in Lung Adenocarcinoma

“…For example, in invasive breast cancer, CD2 was an immune-related prognostic biomarker regulating the tumor microenvironment (25). MNK1/2-eIF4E regulatory axis can affect immunosuppression and metastasis in breast cancer (26). LncRNAs have also been reported to influence the prognosis of many tumors.…”

Application of High-Throughput Imaging Mass Cytometry Hyperion in Cancer Research

“…Analyzing breast cancer cells grafted in different mice model including phospho-eIF4E deficient ones, Guo et al. has pointed the role of MNK1/2-eIF4E axis in the metastatic spreading of post-partum breast cancers and they subsequently used IMC to confirm the presence of high-levels of phospho-eIF4E high-expressing tumor cells and CD8+ T cells with activated dysfunctional phenotype markers in samples of humans with this particular clinical presentation of aggressive breast cancer pointing in this manner a potential new therapeutic target in this field ( 61 ).…”