Seed-and soil-dependent differences in murine breas tumor microenvironments dictate anti-PD-L1 IgG delivery and therapeutic efficacy

Yan Ting Liu, Shreya Goel, Megumi Kai, Jose Alberto Moran Guerrero, Thao Nguyen, Junhua Mai, Haifa Shen, Arturas Ziemys, Kenji Yokoi

Research output: Contribution to journalArticlepeer-review

Abstract

We sought to determine if Stephen Paget’s “seed and soil” hypothesis of organ-preference patterns of cancer metastasis can explain the development of heterogeneity in a tumor microenviron-ment (TME) as well as immunotherapeutic delivery and efficacy. We established single-cell-derived clones (clones 1 and 16) from parental 4T1 murine breast cancer cells to create orthotopic primary and liver metastasis models to deconvolute polyclonal complexity cancer cells and the difference in TME-derived heterogeneities. Tumor-bearing mice were treated with anti-PD-L1 IgG or a control antibody, and immunofluorescent imaging and quantification were then performed to evaluate the therapeutic efficacy on tumor growth, the delivery of therapy to tumors, the development of blood vessels, the expression of PD-L1, the accumulation of immune cells, and the amount of coagulation inside tumors. The quantification showed an inverse correlation between the amount of delivered therapy and therapeutic efficacy in parental-cell-derived tumors. In contrast, tumors originating from clone 16 cells accumulated a significantly greater amount of therapy and responded better than clone-1-derived tumors. This difference was greater when tumors grew in the liver than the primary site. A similar trend was found in PD-L1 expression and immune cell accumulation. However, the change in the number of blood vessels was not significant. In addition, the amount of coagulation was more abundant in clone-1-derived tumors when compared to others. Thus, our findings reconfirmed the seed-and soil-dependent differences in PD-L1 expression, therapeutic delivery, immune cell accumulation, and tumor coagulation, which can constitute a heterogeneous delivery and response of immunotherapy in polyclonal tumors growing in different organs.

Original languageEnglish (US)
Article number530
JournalPharmaceutics
Volume13
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • Drug delivery
  • Heterogeneity
  • Immunotherapy
  • Tumor microenvironment

ASJC Scopus subject areas

  • Pharmaceutical Science

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