Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Nov 1;323(5):C1475-C1495.
doi: 10.1152/ajpcell.00189.2022. Epub 2022 Oct 3.

Breast cancers co-opt normal mechanisms of tolerance to promote immune evasion and metastasis

Lyndsey S Crump  1 , Kelsey T Kines  2   3 , Jennifer K Richer  1   4 , Traci R Lyons  2   3   4
Affiliations
Review

Breast cancers co-opt normal mechanisms of tolerance to promote immune evasion and metastasis

Lyndsey S Crump et al. Am J Physiol Cell Physiol. .

Abstract

Normal developmental processes, such as those seen during embryonic development and postpartum mammary gland involution, can be reactivated by cancer cells to promote immune suppression, tumor growth, and metastatic spread. In mammalian embryos, paternal-derived antigens are at risk of being recognized as foreign by the maternal immune system. Suppression of the maternal immune response toward the fetus, which is mediated in part by the trophoblast, is critical to ensure embryonic survival and development. The postpartum mammary microenvironment also exhibits immunosuppressive mechanisms accompanying the massive cell death and tissue remodeling that occurs during mammary gland involution. These normal immunosuppressive mechanisms are paralleled during malignant transformation, where tumors can develop neoantigens that may be recognized as foreign by the immune system. To circumvent this, tumors can dedifferentiate and co-opt immune-suppressive mechanisms normally utilized during fetal tolerance and postpartum mammary involution. In this review, we discuss those similarities and how they can inform our understanding of cancer progression and metastasis.

Keywords: cancer; inflammation; involution; macrophages; pregnancy.

PubMed Disclaimer

Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Chi3l1 and Ho-1 during mammary gland involution. Microarray analysis of (A) Hmox1 and (B) Chi3l1 mRNA expression from mice that are virgin [V, (day 8 from the study by Clarkson et al. (59) and day 10 from the study by Stein et al. (58)] or undergoing postpartum mammary gland involution (I; days 1–4). *P < 0.05, **P < 0.005 via ANOVA with Tukey’s multiple-comparisons test. Data from the study by Clarkson et al. (pink) (59) and Stein et al. (black) (58).
Figure 2.
Figure 2.
Parallels between the immune-suppressive milieu at the maternal-fetal interface, in the involution mammary microenvironment, and during breast tumorigenesis. Immune cells and immune-suppressive factors (e.g., TDO2 metabolites, HO-1 metabolites, cytokines, and other secreted factors including CHI3L1, SEMA7A, and PGE2) are shown in (A) the maternal endometrial decidua, (B) during mammary gland involution, and (C) in the breast tumor microenvironment. CHI3L1, chitinase 3-like-1; HO-1, heme oxygenase 1; MDSC, myeloid-derived suppressor cell; NK, natural killer; PGE2, Prostaglandin E2; SEMA7A, semaphorin 7a; TAM, tumor-associated macrophage; TDO2, tryptophan 2,3-dioxygenase. This figure was created with BioRender.com.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Tafuri A, Alferink J, Möller P, Hämmerling GJ, Arnold B. T cell awareness of paternal alloantigens during pregnancy. Science 270: 630–633, 1995. doi:10.1126/science.270.5236.630. - DOI - PubMed
    1. Guerin LR, Prins JR, Robertson SA. Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment? Hum Reprod Update 15: 517–535, 2009. doi:10.1093/humupd/dmp004. - DOI - PMC - PubMed
    1. Ashkar AA, Black GP, Wei Q, He H, Liang L, Head JR, Croy BA. Assessment of requirements for IL-15 and IFN regulatory factors in uterine NK cell differentiation and function during pregnancy. J Immunol 171: 2937–2944, 2003. doi:10.4049/jimmunol.171.6.2937. - DOI - PubMed
    1. Greenwood JD, Minhas K, di Santo JP, Makita M, Kiso Y, Croy BA. Ultrastructural studies of implantation sites from mice deficient in uterine natural killer cells. Placenta 21: 693–702, 2000. doi:10.1053/plac.2000.0556. - DOI - PubMed
    1. Tamburini BAJ, Elder AM, Finlon JM, Winter AB, Wessells VM, Borges VF, Lyons TR. PD-1 blockade during post-partum involution reactivates the anti-tumor response and reduces lymphatic vessel density. Front Immunol 10: 1313, 2019. doi:10.3389/fimmu.2019.01313. - DOI - PMC - PubMed

Publication types