TY - JOUR
T1 - The MNK1/2–eIF4E axis supports immune suppression and metastasis in postpartum breast cancer
AU - Guo, Qianyu
AU - Bartish, Margarita
AU - Gonçalves, Christophe
AU - Huang, Fan
AU - Smith-Voudouris, Julian
AU - Krisna, Sai Sakktee
AU - Preston, Samuel E. J.
AU - Emond, Audrey
AU - Li, Vivian Z.
AU - Duerr, Claudia U.
AU - Gui, Yirui
AU - Cleret-Buhot, Aurelie
AU - Thebault, Pamela
AU - Lefrere, Hanne
AU - Lenaerts, Liesbeth
AU - Plourde, Dany
AU - Su, Jie
AU - Mindt, Barbara C.
AU - Hewgill, Shannon A.
AU - Cotechini, Tiziana
AU - Hindmarch, Charles C. T.
AU - Yang, William
AU - Khoury, Elie
AU - Zhan, Yao
AU - Narykina, Valeria
AU - Wei, Yuhong
AU - Floris, Giuseppe
AU - Basik, Mark
AU - Amant, Frederic
AU - Quail, Daniela F.
AU - Lapointe, Rejean
AU - Fritz, Jorg H.
AU - del Rincon, Sonia V.
AU - Miller, Wilson H.
N1 - Funding Information: This research is funded by the Canadian Institutes of Health Research (grants MOP-142281 to W.H. Miller Jr; PJT-156269 to W.H. Miller Jr, S.V. del Rincon, and J. H. Fritz; and PJT-162260 to S.V. del Rincon and J.H. Fritz) and the Cancer Research Society and CURE Foundation (grant 20239 to W.H. Miller Jr). This work was also supported by a grant from McGill Interdisciplinary Initiative in Infection and Immunity (Mi4) to S.V. del Rincon. The research was further supported by the Rossy Cancer Network. F. Amant is senior researcher for the Research Fund Flanders Funding Information: M. Basik reports grants from Canadian Cancer Society during the conduct of the study, as well as grants from LabCorp and Pfizer outside the submitted work. J.H. Fritz reports grants from Canadian Institutes of Health Research (CIHR) during the conduct of the study. W.H. Miller Jr reports personal fees from Merck, Bristol Myers Squibb, Roche, Novartis, Amgen, GlaxoSmithKline, Mylan, and EMD Serono, and grants from Merck and Bristol Myers Squibb (to institution) outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: 2021 American Association for Cancer Research
PY - 2021/7/15
Y1 - 2021/7/15
N2 - 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 prometastatic mRNAs in tumor cells, but its role in modulating the function of nontumor 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 protumor function of select cells of the tumor microenvironment. PPBC mice deficient for phospho-eIF4E (eIF4ES209A) were protected against lung metastasis and exhibited differences in the tumor and lung immune microenvironment compared with wild-type mice. Moreover, the expression of fibroblast-derived IL33, 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 CD8þ 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.
AB - 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 prometastatic mRNAs in tumor cells, but its role in modulating the function of nontumor 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 protumor function of select cells of the tumor microenvironment. PPBC mice deficient for phospho-eIF4E (eIF4ES209A) were protected against lung metastasis and exhibited differences in the tumor and lung immune microenvironment compared with wild-type mice. Moreover, the expression of fibroblast-derived IL33, 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 CD8þ 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.
UR - http://www.scopus.com/inward/record.url?scp=85110362908&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/0008-5472.CAN-20-3143
DO - https://doi.org/10.1158/0008-5472.CAN-20-3143
M3 - Article
C2 - 33975880
SN - 0008-5472
VL - 81
SP - 3876
EP - 3889
JO - Cancer research
JF - Cancer research
IS - 14
ER -