Mammary Tumor–Derived Transplants as Breast Cancer Models to Evaluate Tumor–Immune Interactions and Therapeutic Responses

Moore, Jade; Ma, Lin; Lazar, Ann; Barcellos-Hoff, Mary Helen

doi:10.1158/0008-5472.can-21-0253

Cited by 4 publications

(4 citation statements)

References 52 publications

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“…3A ). mTDT are classified as A-L based on parental tumor origin 37 . Mice bearing F mTDT tumors with an average volume of approximately 75 mm 3 were randomized into treatment arms consisting of radiotherapy (RT), anti-PD-L1 or TGFβi, dual combinations, or triple treatment (combination plus radiation).…”

Section: Resultsmentioning

confidence: 99%

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Lack of TGFβ signaling competency predicts immune poor cancer conversion to immune rich and response to checkpoint blockade

Moore,

Gkantalis,

Guix

et al. 2024

Preprint

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Background: Transforming growth factor beta (TGFbeta) is well-recognized as an immunosuppressive player in the tumor microenvironment but also has a significant impact on cancer cell phenotypes. Loss of TGFbeta signaling impairs DNA repair competency, which is described by a transcriptomic score, BAlt. Cancers with high BAlt have more genomic damage and are more responsive to genotoxic therapy. The growing appreciation that cancer DNA repair deficits are important determinants of immune response prompted us to investigate BAlts association with response to immune checkpoint blockade (ICB). We predicted that high BAlt tumors would be infiltrated with lymphocytes because of DNA damage burden and hence responsive to ICB. Methods: We analyzed public transcriptomic data from clinical trials and preclinical models using transcriptomic signatures of TGFbeta; targets, DNA repair genes, tumor educated immune cells and interferon. A high BAlt, immune poor mammary tumor derived transplant model resistant to programmed death ligand 1 (PD-L1) antibodies was studied using multispectral flow cytometry to interrogate the immune system. Results: Metastatic bladder patients in IMvigor 210 who responded to ICB had significantly increased BAlt scores and experienced significantly longer overall survival compared to those with low BAlt scores (hazard ratio 0.62, P=0.011). Unexpectedly, 75% of high BAlt cancers were immune poor as defined by low expression of tumor educated immune cell and interferon signatures. The association of high BAlt with immune poor cancer was also evident in TCGA and preclinical cancer models. We used a high BAlt, immune poor cancer to test therapeutic strategies to overcome its inherent anti-PD-L1 resistance. Combination treatment with radiation and TGFB; inhibition was necessary for lymphocytic infiltration and activated NK cells were required for ICB response. Bioinformatic analysis identified high BAlt, immune poor B16 and CT26 preclinical models and paired biopsies of cancer patients that also demonstrated NK cell activation upon response to ICB. Conclusions: Our studies confirm BAlt as a biomarker that predicts response to ICB in immune poor cancers, which has implications for the development of therapeutic strategies to increase the number of cancer patients who will benefit from immunotherapy.

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Section: Resultsmentioning

confidence: 99%

“…For treatment experiments, 8-10-week-old mice were transplanted orthotopically with F2 mTDT from family F previously described 37 . For all experiments, mice were palpated three times a week until tumor reached 2x2 and then daily upon randomization into treatment groups when tumor reached 65-100mm 3 .…”

Section: Mammary Tumor-derived Transplants (Mtdt)mentioning

confidence: 99%

Lack of TGFβ signaling competency predicts immune poor cancer conversion to immune rich and response to checkpoint blockade

Moore,

Gkantalis,

Guix

et al. 2024

Preprint

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“…This partly explains why upregulation of METTL7A is associated with extended overall survival ( Archilla-Ortega et al, 2022 ). In addition, the increase in TIL was reported to have a significant improvement in the response of patients to immunotherapy ( Moore et al, 2022 ; Qiao et al, 2022 ). Thus, we postulated that upregulation of METTL7A could enhance the efficacy of immunotherapy.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic characterization revealed that METTL7A inhibits melanoma progression via the p53 signaling pathway and immunomodulatory pathway

Zhang

Zou

Liu

et al. 2023

PeerJ

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METTL7A is a protein-coding gene expected to be associated with methylation, and its expression disorder is associated with a range of diseases. However, few research have been carried out to explore the relationship between METTL7A and tumor malignant phenotype as well as the involvement potential mechanism. We conducted our research via a combination of silico analysis and molecular biology techniques to investigate the biological function of METTL7A in the progression of cancer. Gene expression and clinical information were extracted from the TCGA database to explore expression variation and prognostic value of METTL7A. In vitro, CCK8, transwell, wound healing and colony formation assays were conducted to explore the biological functions of METT7A in cancer cell. GSEA was performed to explore the signaling pathway involved in METTL7A and validated via western blotting. In conclusion, METTL7A was downregulated in most cancer tissues and its low expression was associated with shorter overall survival. In melanoma, METTL7A downregulation was associated with poorer clinical staging, lower levels of TIL infiltration, higher IC50 levels of chemotherapeutic agents, and poorer immunotherapy outcomes. QPCR results confirm that METTL7A is down-regulated in melanoma cells. Cell function assays showed that METTL7A knockdown promoted proliferation, invasion, migration and clone formation of melanoma cells. Mechanistic studies showed that METTL7A inhibits tumorigenicity through the p53 signaling pathway. Meanwhile, METTL7A is also a potential immune regulatory factor.

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“…On the other hands, the limitation of microscope detection devices was reduced fluorescent signal visibility, leading to incomplete interpretation in digital images. Advanced detectors can expand the dynamic range of signal detection, but their high cost limits their use in routine clinical practices 40 , 41 . HDR processing has been applied in various studies to overcome imaging limitations, including embryonic anatomy and organ function evaluation 23 , 42 – 44 .…”

Section: Discussionmentioning

confidence: 99%

Optimizing immunofluorescence with high-dynamic-range imaging to enhance PD-L1 expression evaluation for 3D pathology assessment from NSCLC tumor tissue

Huang,

Kuo,

Hung

et al. 2024

Sci Rep

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Assessing programmed death ligand 1 (PD-L1) expression through immunohistochemistry (IHC) is the golden standard in predicting immunotherapy response of non-small cell lung cancer (NSCLC). However, observation of heterogeneous PD-L1 distribution in tumor space is a challenge using IHC only. Meanwhile, immunofluorescence (IF) could support both planar and three-dimensional (3D) histological analyses by combining tissue optical clearing with confocal microscopy. We optimized clinical tissue preparation for the IF assay focusing on staining, imaging, and post-processing to achieve quality identical to traditional IHC assay. To overcome limited dynamic range of the fluorescence microscope’s detection system, we incorporated a high dynamic range (HDR) algorithm to restore the post imaging IF expression pattern and further 3D IF images. Following HDR processing, a noticeable improvement in the accuracy of diagnosis (85.7%) was achieved using IF images by pathologists. Moreover, 3D IF images revealed a 25% change in tumor proportion score for PD-L1 expression at various depths within tumors. We have established an optimal and reproducible process for PD-L1 IF images in NSCLC, yielding high quality data comparable to traditional IHC assays. The ability to discern accurate spatial PD-L1 distribution through 3D pathology analysis could provide more precise evaluation and prediction for immunotherapy targeting advanced NSCLC.

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Mammary Tumor–Derived Transplants as Breast Cancer Models to Evaluate Tumor–Immune Interactions and Therapeutic Responses

Abstract: Gene expression data are archived in gene expression omnibus (GEO, RRID: SCR_005012) under accession number GSE152403.Research.

Cited by 4 publications

References 52 publications

Lack of TGFβ signaling competency predicts immune poor cancer conversion to immune rich and response to checkpoint blockade

Lack of TGFβ signaling competency predicts immune poor cancer conversion to immune rich and response to checkpoint blockade

Transcriptomic characterization revealed that METTL7A inhibits melanoma progression via the p53 signaling pathway and immunomodulatory pathway

Optimizing immunofluorescence with high-dynamic-range imaging to enhance PD-L1 expression evaluation for 3D pathology assessment from NSCLC tumor tissue

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