Immunologically “cold” triple negative breast cancers engraft at a higher rate in patient derived xenografts

Petrosyan, Varduhi; Dobrolecki, Lacey E.; LaPlante, Emily L.; Srinivasan, Ramakrishnan Rajaram; Bailey, Matthew H.; Welm, Alana L.; Welm, Bryan E.; Lewis, Michael T.; Milosavljevic, Aleksandar

doi:10.1038/s41523-022-00476-0

Cited by 8 publications

(6 citation statements)

References 47 publications

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“…One assumption of previous PDX studies has been that the success or failure of a single tumour region represents the behaviour of the tumour overall. However, we find that distinct spatial regions of the same tumour can have divergent outcomes in PDX models, and that engraftment is correlated with tumour purity and inversely associated with T cell infiltration, consistent with a study of breast cancer PDX models 37 . Prior studies also suggest that lung squamous carcinomas more readily give rise to PDX than lung adenocarcinomas [16][17][18][19] .…”

Section: Discussionsupporting

confidence: 90%

Genomic evolution of non-small cell lung cancer patient-derived xenograft models

Hynds

Huebner

Pearce

et al. 2023

Preprint

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Patient-derived xenograft (PDX) models of cancer, developed through injection of patient tumour cells into immunocompromised mice, have been widely adopted in preclinical studies, as well as in precision oncology approaches. However, the extent to which PDX models represent the underlying genetic diversity of a patient's tumour and the extent of on-going genomic evolution in PDX models are incompletely understood, particularly in the context of heterogeneous cancers such as non-small cell lung cancer (NSCLC). To investigate the depiction of intratumour heterogeneity by PDX models, we derived 47 new subcutaneous multi-region PDX models from 22 patients with primary NSCLC enrolled in the clinical longitudinal cohort study TRACERx. By analysing whole exome sequencing data from primary tumours and PDX models, we find that PDX establishment creates a genomic bottleneck, with 76% of PDX models being derived from a single primary tumour subclone. Despite this, multiple primary tumour subclones were capable of PDX establishment in regional PDX models, indicating that PDX libraries derived from multiple tumour regions can capture intratumour heterogeneity. Acquisition of somatic mutations continued during PDX model expansion, and was associated with APOBEC- or mismatch repair deficiency-induced mutational signatures in a subset of models. Overall, while NSCLC PDX models retain truncal genomic alterations, the absence of subclonal heterogeneity representative of the primary tumour is a major limitation. Our results emphasise the importance of characterising and monitoring intratumour heterogeneity in the context of pre-clinical cancer studies.

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Section: Discussionsupporting

confidence: 90%

Genomic evolution of non-small cell lung cancer patient-derived xenograft models

Hynds

Huebner

Pearce

et al. 2023

Preprint

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“…As shown in Figure 6D, both CD4 + T cells and CD8 + T cells were scarcely detected in the control group, indicating that TNBC represents an immune “cold” tumor with minimal T cell infiltration. [ 35,36 ] Conversely, all treatment groups displayed a marked increase in T cell infiltration, with the aPD‐1/PTX NPs@MNs group registering the highest infiltration. Immunofluorescence staining for CD8 + T cells yielded congruent findings (Figure S7, Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

Microneedles‐Mediated Intradermal Delivery of Paclitaxel/Anti‐PD‐1 for Efficient and Safe Triple‐Negative Breast Cancer Therapy

Wang,

Wen,

Chen

et al. 2024

Advanced Therapeutics

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Triple‐negative breast cancer (TNBC) remains one of the most fatal diseases in human populations, characterized by a high incidence and mortality rate. Although the conjunction of chemotherapeutic agents, like albumin‐bound paclitaxel (nab‐PTX), and immune checkpoint inhibitors, exemplified by the anti‐PD‐1 antibody (aPD‐1), has surfaced as a promising modality for TNBC treatment, the optimization of their synergistic therapeutic impact while concurrently curtailing associated adverse reactions poses a persistent challenge. Here, we developed a soluble microneedle (MN) delivery platform (designated as aPD‐1/PTX NPs@MN) for the co‐delivery of nab‐PTX and aPD‐1. The soluble MN‐based delivery system is anticipated to enhance the local accumulation of therapeutic agents, reducing the adverse effects associated with systemic administration. Simultaneously, heightened concentrations of glutathione (GSH) within the tumor microenvironment (TME) may trigger the liberation of nab‐PTX and aPD‐1, inducing ICD to promote antitumor T cells infiltration and activation by blocking the immunosuppressive PD‐1 pathway, potentially culminating in a triumphant chemoimmunotherapy strategy for TNBC.This article is protected by copyright. All rights reserved

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“…C1P levels are not significantly different in tumor tissue than normal tissues, although some studies have shown higher C1P/CERK levels in lung or pancreatic cancer cells and lower in oral squamous cell carcinoma 44,45 . As C1P is known to cause inflammation, lower C1P levels in TNBC tissues as compared to luminal tissue can be correlated to its “COLD” immunosuppressive nature due to poor infiltration of immune cells specially CD3 and CD8 T cell types 46 . Therefore, role of C1P in proliferation, inflammation, and metastasis depends on cancer cell type and context.…”

Section: Discussionmentioning

confidence: 99%

“…immunosuppressive nature due to poor infiltration of immune cells specially CD3 and CD8 T cell types. 46 Therefore, role of C1P in proliferation, inflammation, and metastasis depends on cancer cell type and context. Different chain-length ceramides have been shown to exert opposing effects in various cancer models where decrease in ceramide synthesis through sphingomyelin hydrolysis inhibited tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Unique sphingolipid signature identifies luminal and triple‐negative breast cancer subtypes

Kar

Medatwal

Rajput

et al. 2023

Intl Journal of Cancer

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Breast cancer (luminal and triple-negative breast cancer [TNBC]) is the most common cancer among women in India and worldwide. Altered sphingolipid levels have emerged as a common phenomenon during cancer progression. However, these alterations are yet to be translated into robust diagnostic and prognostic markers for cancer. Here, we present the quantified sphingolipids of tumor and adjacent-normal tissues from patients of luminal (n = 70) and TNBC (n = 42) subtype from an Indian cohort using targeted liquid chromatography mass spectrometry. We recorded unique sphingolipid profiles that distinguished luminal and TNBC tumors in comparison to adjacent normal tissue by six-sphingolipid signatures. Moreover, systematic comparison of the profiles of luminal and TNBC tumors provided a unique fivesphingolipid signature distinguishing the two subtypes. We further identified key sphingolipids that can stratify grade II and grade III tumors of luminal and TNBC subtype as well as their lymphovascular invasion status. Therefore, we provide the right evidence to develop these candidate sphingolipids as widely acceptable marker/s capable of diagnosing luminal vs TNBC subtype of breast cancer, and predicting the disease severity by identifying the tumor grade.

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Immunologically “cold” triple negative breast cancers engraft at a higher rate in patient derived xenografts

Cited by 8 publications

References 47 publications

Genomic evolution of non-small cell lung cancer patient-derived xenograft models

Genomic evolution of non-small cell lung cancer patient-derived xenograft models

Microneedles‐Mediated Intradermal Delivery of Paclitaxel/Anti‐PD‐1 for Efficient and Safe Triple‐Negative Breast Cancer Therapy

Unique sphingolipid signature identifies luminal and triple‐negative breast cancer subtypes

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