Abstract LT004: Immune suppression established by postpartum liver involution promotes liver metastasis
Authors: Quackenbush Alexandra , Penncok Nathan , Schedin Pepper 
Published: March 2021

Abstract
A postpartum diagnosis of breast cancer in women ≤45 yoa is an independent predictor of liver metastasis, suggesting a liver metastatic advantage (PMID: 27974414). In rodents, we identified a postpartum liver biology that supports liver metastasis in mouse models. This biology is weaning-induced liver involution and is characterized by a transient period of hepatocyte cell death, catabolic metabolism, immune influx, and stromal remodeling (PMID: 27974414). Here, we sought to investigate the mechanism by which post-wean liver involution supports breast cancer metastasis. Liver metastases were induced by portal vein injection of mouse mammary tumor cells into nulliparous or post-wean, involution hosts (PMID: 28060292). Compared to nulliparous mice, involution mice had increased incidence of liver metastasis, as well as more liver lesions per mouse. However, there was no group differences in tumor size or proliferation index. These data are consistent with the involution liver providing an environment that promotes tumor cell establishment, not proliferation. To further investigate, we intraportally injected GFP-tagged tumor cells into GFP-tolerant mice, and assessed tumor cell abundance in the liver at 90 minutes, and 1, 3, and 14 days post injection. Contrary to our expectations, the nulliparous group had more tumor cells present at 90 minutes, 1 day, and 3 days post tumor cell injection. We saw the metastatic advantage in the involution group emerge by 14 days after tumor cell injection. We also observed increased abundance of PD1+ CD4 T cells in addition to heightened IL-10 signaling in the involution group at baseline (i.e. no tumor). Based on these observations, we hypothesized that the involution metastatic niche may be characterized by immune suppression, permitting tumor cell escape from immune surveillance. To address if the involution host liver is immune suppressed, we used an in vivo T cell activation assay where we adoptively transferred antigen-specific T cells systemically, and subsequently injected the cognate antigen into the liver of tumor free mice. Five days later, we assessed antigen-specific T cell number as a measure of T cell priming and activation. We found significantly impaired naïve T cell priming in the normal involution host liver compared to the nulliparous host. These data raise the possibility that impaired adaptive immunity could be responsible for increased liver metastasis in the involution group. In support, when we depleted CD8 T cells in our liver metastasis model, we found that metastasis in the anti-CD8 treated nulliparous group was similar to the untreated involution group, showing that depletion of cytotoxic immune cells in nulliparous hosts can recapitulate the involution host metastatic advantage. Taken together, our findings suggest the normal postpartum liver is in an immune suppressed state, which can provide a pro-metastatic advantage to circulating breast cancer cells. Future work will investigate therapeutic targeting of the postpartum liver niche.
Citation Format: Alexandra Quackenbush, Nathan Penncok, Pepper Schedin. Immune suppression established by postpartum liver involution promotes liver metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT004.