Single-cell RNA-sequencing identifies anti-cancer immune phenotypes in the early lung metastatic niche during breast cancer

Orbach, Sophia M.; Brooks, Michael; Zhang, Yining; Campit, Scott; Bushnell, Grace G.; Decker, Joseph T.; Rebernick, Ryan; Chandrasekaran, Sriram; Wicha, Max S.; Jeruss, Jacqueline S.; Shea, Lonnie D.

doi:10.1007/s10585-022-10185-4

Cited by 8 publications

(9 citation statements)

References 91 publications

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“…Among the hallmark gene sets (Figure 1d), most pathways exhibited opposing trends between 4T07 and 67NR tumors relative to 4T1 (e.g., complement, KRAS signaling) or were comparable between 4T1 and the nonmetastatic tumors (e.g., reactive oxygen species pathway, apoptosis). A noticeable exception is the down‐regulation of the interferon‐gamma response in the 4T1 tumors, which is consistent with our previous reports identifying anti‐cancer activity associated with interferon signaling 45,46 . Overall, these results indicate clear differences in the primary tumors; however, these differences are indicative of the inoculated cells rather than the microenvironment.…”

Section: Resultssupporting

confidence: 91%

“…A noticeable exception is the downregulation of the interferon-gamma response in the 4T1 tumors, which is consistent with our previous reports identifying anti-cancer activity associated with interferon signaling. 45,46 Overall, these results indicate clear differences in the primary tumors; however, these differences are indicative of the inoculated cells rather than the microenvironment.…”

Section: The Primary Tumor Microenvironment Poorly Correlates With Me...mentioning

confidence: 78%

“…Reproducibility and efficacy across disease progression were established by validating the signature by PCR on the scaffolds in a separate cohort of mice at 7, 14, and 21‐days post‐inoculation, which corresponds to the pre‐metastatic niche, early metastatic niche, and metastatic niche, respectively in the 4T1 models 45 . When considering the individual genes in the signature, each was significantly up‐regulated at day 21 in the 4T1 scaffolds relative to the 67NR and 4T07 scaffolds (Figure 4c).…”

Section: Resultsmentioning

confidence: 99%

“…Scaffolds were implanted through a small incision made on the upper back of the mice, which was sealed with sterile wound clips (Reflex 7 mm). Scaffolds were allowed to equilibrate in the subcutaneous space for 2 weeks before the mice received 50 μL orthotopic inoculations of 67NR, 4T07, or 4T1 cells at a concentration of 40 million cells/mL phosphate buffered saline (PBS) in the fourth, right mammary fat pad (2 million cells/mouse) 25–27,31,45 . Tumors were allowed to progress for 7‐, 14‐ or 21‐days post‐inoculation.…”

Section: Methodsmentioning

confidence: 99%

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An engineered niche delineates metastatic potential of breast cancer

Orbach,

DeVaull,

Bealer

et al. 2023

Bioengineering & Transla Med

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Metastatic breast cancer is often not diagnosed until secondary tumors have become macroscopically visible and millions of tumor cells have invaded distant tissues. Yet, metastasis is initiated by a cascade of events leading to formation of the pre‐metastatic niche, which can precede tumor formation by a matter of years. We aimed to distinguish the potential for metastatic disease from nonmetastatic disease at early times in triple‐negative breast cancer using sister cell lines 4T1 (metastatic), 4T07 (invasive, nonmetastatic), and 67NR (nonmetastatic). We used a porous, polycaprolactone scaffold, that serves as an engineered metastatic niche, to identify metastatic disease through the characteristics of the microenvironment. Analysis of the immune cell composition at the scaffold was able to distinguish noninvasive 67NR tumor‐bearing mice from 4T07 and 4T1 tumor‐bearing mice but could not delineate metastatic potential between the two invasive cell lines. Gene expression in the scaffolds correlated with the up‐regulation of cancer hallmarks (e.g., angiogenesis, hypoxia) in the 4T1 mice relative to 4T07 mice. We developed a 9‐gene signature (Dhx9, Dusp12, Fth1, Ifitm1, Ndufs1, Pja2, Slc1a3, Soga1, Spon2) that successfully distinguished 4T1 disease from 67NR or 4T07 disease throughout metastatic progression. Furthermore, this signature proved highly effective at distinguishing diseased lungs in publicly available datasets of mouse models of metastatic breast cancer and in human models of lung cancer. The early and accurate detection of metastatic disease that could lead to early treatment has the potential to improve patient outcomes and quality of life.

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Section: Resultssupporting

confidence: 91%

Section: The Primary Tumor Microenvironment Poorly Correlates With Me...mentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

An engineered niche delineates metastatic potential of breast cancer

Orbach,

DeVaull,

Bealer

et al. 2023

Bioengineering & Transla Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, adenosine metabolism of neutrophils was observed to be shifted to inosine metabolism in pre-metastatic niche over time. Finally, extracellular inosine molecules inhibit the production of inflammatory cytokines, which weakens antitumor immune function [ 81 ]. Rice et al showed that oxidative mitochondrial metabolism is possible for neutrophil subsets with c-Kit + .…”

Section: Metabolic Changes Of Tansmentioning

confidence: 99%

The role and metabolic adaptations of neutrophils in premetastatic niches

Chen

2023

Biomark Res

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It has been found that tumor cells create microenvironments in distant organs that promote their survival and growth in advance of their arrival. These predetermined microenvironments are referred to as “pre-metastatic niches”. Increasing attention is being paid to neutrophils’ role in forming the pre-metastatic niche. As major components of the pre-metastatic niche, tumor-associated neutrophils (TANs) play an important role in the formation of the pre-metastatic niche through communication with multiple growth factors, chemokines, inflammatory factors, and other immune cells, which together create a pre-metastatic niche well suited for tumor cell seeding and growth. However, how TANs modulate their metabolism to survive and exert their functions in the process of metastasis remains largely to be discovered. Accordingly, the objective of this review is to assess the role that neutrophils play in the formation of pre-metastatic niche and to explore the metabolism alteration of neutrophils in cancer metastasis. A better understanding of the role of TANs in pre-metastatic niche will help us discover new mechanisms of metastasis and develop new therapies targeting TANs.

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Engineered immunologic niche monitors checkpoint blockade response and probes mechanisms of resistance

Raghani,

Urie,

et al. 2024

ImmunoMedicine

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Antibodies to programmed cell death protein 1 (anti‐PD‐1) have become a promising immunotherapy for triple negative breast cancer (TNBC), blocking PD‐L1 signaling from pro‐tumor cells through T cell PD‐1 receptor binding. Nevertheless, only 10%–20% of PD‐L1+ metastatic TNBC patients who meet criteria benefit from immune checkpoint blockade (ICB), and biomarkers to predict patient response have been elusive. We have previously developed an immunological niche, consisting of a microporous implant in the subcutaneous space, that supports tissue formation whose immune composition is consistent with that within vital organs. Herein, we investigated dynamic gene expression within this immunological niche to provide biomarkers of response to anti‐PD‐1. In a 4T1 model of metastatic TNBC, we observed sensitivity and resistance to anti‐PD‐1 based on primary tumor growth and survival. The niche was biopsied before, during, and after anti‐PD‐1 therapy, and analyzed for cell types and gene expression indicative of treatment refractivity. Myeloid cell‐to‐lymphocyte ratios were altered between ICB‐sensitivity and resistance. Longitudinal analysis of gene expression implicated dynamic myeloid cell function that stratified sensitivity from resistance. A niche‐derived gene signature predicted sensitivity or resistance prior to therapy. Analysis of the niche to monitor immunotherapy response presents a new opportunity to personalize care and investigate mechanisms underlying treatment resistance.Summary: A remote implant identified biomarkers that predict anti‐PD‐1 response before therapy, providing a unique tool to understand heterologous immunotherapy resistance in triple negative breast cancer.

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Single-cell RNA-sequencing identifies anti-cancer immune phenotypes in the early lung metastatic niche during breast cancer

Cited by 8 publications

References 91 publications

An engineered niche delineates metastatic potential of breast cancer

An engineered niche delineates metastatic potential of breast cancer

The role and metabolic adaptations of neutrophils in premetastatic niches

Engineered immunologic niche monitors checkpoint blockade response and probes mechanisms of resistance

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