Assessing Tumor-Infiltrating Lymphocytes in Breast Cancer: A Proposal for Combining Immunohistochemistry and Gene Expression Analysis to Refine Scoring

Locy, Hanne; Verhulst, Stefaan; Cools, Wilfried; Waelput, Wim; Brock, Stefanie; Cras, Louise; Schiettecatte, Ann; Jonckheere, Jan; Grunsven, Leo A. van; Vanhoeij, Marian; Thielemans, Kris; Breckpot, Karine

doi:10.3389/fimmu.2022.794175

Cited by 19 publications

(15 citation statements)

References 67 publications

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“…In addition, many studies have reported that an intense TILs infiltration is associated with progression of disease [5,48,49]. Increasing levels of TILs have been associated with improved therapy outcome in HER2+ breast cancer and/or triple negative breast cancer patients [57]. Furthermore, we observed highly similar distribution pattern of CD56 + cells in the core tissue sample of healthy donor and breast cancer subtypes (Figure 2A).…”

Section: Our Results Clearly Indicate Significantly Decreased Express...supporting

confidence: 67%

Differences in tolerogenic status of NK cells between luminal A type, luminal B type, and triple-negative breast cancer

Starčević¹,

Grebić²,

Avirović³

et al. 2022

neo

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Globally, breast cancer is the main cause of death among female cancer patients. The tumorinfiltrating lymphocytes (TILs) in breast cancer are associated with a more favorable outcome of a disease. Natural killer (NK) cells are important cytotoxic cells involved in tumor immunosurveillance, causing the direct killing of tumor cells. In solid tumors, peripheral NK cells and tumor-infiltrating NK cells display an altered characterized by reduced cytotoxicity or anergy. The goal of this study was to investigate the NK cells' phenotype and activation status in order to get into the pathological process of breast cancer subtypes. In our study, the normal tissues and tumoral breast tissue were fixed in formalin, embedded in paraffin, and the phenotypic marker CD56 and proinflammatory cytokine IL-15 were identified by immunohistology. The distribution and expression of receptors repertoire (NKG2A, NKG2C, NKp46, CD94, CD69, and CD107a) were investigated in peripheral NK cells of mononuclear cells by flow cytometry. mRNA of cytolytic mediators was determined by real-time PCR. The frequency of CD56+ and IL-15+ cells were significantly higher in triple-negative breast cancer tissue. The frequency of NK cell activating receptors was decreased in investigated breast cancer subtypes while the inhibitory NKG2A receptor was increased. Decreased percentage of CD69+/CD107a+ in NK cells could indicate lower cellular activation and cytotoxicity. In luminal B breast cancer, the mRNA of cytolytic mediators was upregulated. In conclusion, modulation of activation status in tumor-infiltration NK cells could be involved in the pathogenesis of molecular breast cancer subtypes. This highlights the importance of NK cells as an appropriate target for potent anti-tumor response in the immunosuppressive tumor microenvironment of breast cancer.

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Section: Our Results Clearly Indicate Significantly Decreased Express...supporting

confidence: 67%

Differences in tolerogenic status of NK cells between luminal A type, luminal B type, and triple-negative breast cancer

Starčević¹,

Grebić²,

Avirović³

et al. 2022

neo

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“…Immune infiltration has been noted as a characteristic of gcGBM (53,66,67). As the prognostic role of CD3 and CD8 have yet to be established in gcGBM, there are numerous reports associating infiltrating lymphocytes with improved prognosis for several cancers (68)(69)(70)(71). In our analysis, both CD3 and CD8 proteins were expressed at least two-fold higher in several CD45-enriched AOIs of gcGBM compared to the same type of AOI in GBM samples (Fig.…”

Section: Glioblastoma Study Using Spatial Proteogenomic Assaymentioning

confidence: 54%

Ultra High-Plex Spatial Proteogenomic Investigation of Giant Cell Glioblastoma Multiforme Immune Infiltrates Reveals Distinct Protein and RNA Expression Profiles

Bonnett

Rosenbloom

Ong

et al. 2022

Preprint

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A deeper understanding of complex biological processes, including tumor development and immune response, requires ultra high-plex, spatial interrogation of multiple 'omes'. Here we present the development and implementation of a novel spatial proteogenomic (SPG) assay on the GeoMx® Digital Spatial Profiler platform with NGS readout that enables ultra high-plex digital quantitation of proteins (> 100-plex) and RNA (whole transcriptome, > 18,000-plex) from a single FFPE sample. This study highlighted the high concordance, R > 0.85, and <11% change in sensitivity between SPG assay and the single analyte assays on various cell lines and tissues from human and mouse. Furthermore, we demonstrate that the SPG assay was reproducible across multiple users. When used in conjunction with advanced cellular neighborhood segmentation, distinct immune or tumor RNA and protein targets were spatially resolved within individual cell subpopulations in human colorectal cancer and non-small cell lung cancer. We used the SPG assay to interrogate 23 different glioblastoma multiforme samples across 4 pathologies. The study revealed distinct clustering of both RNA and protein based on pathology and anatomic location. The in-depth investigation of giant cell glioblastoma multiforme revealed distinct protein and RNA expression profiles compared to that of the more common glioblastoma multiforme. More importantly, the use of spatial proteogenomics allowed simultaneous interrogation of critical protein post-translational modifications alongside whole transcriptomic profiles within the same distinct cellular neighborhoods.

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“…In the case of BC, immune cells invade the cancer tissue, and infiltrating lymphocytes play a central in cancer growth, so that the percentage of TILs is currently accepted as a useful prognostic factor for managing breast cancer patients. Histological methods (hematoxylin–eosin or immunohistochemistry staining) are used to evaluate the TILs percentage in paraffin-embedded BC tissue sections [ 28 , 32 ]. Although the assessment is specific to the tumor region, it does not consider the different subpopulations infiltrating the tumor, unless time-consuming and rather complex analyses are made (i.e., IHC with specific markers for each subpopulation).…”

Section: Discussionmentioning

confidence: 99%

Identification of Immune Cell Components in Breast Tissues by a Multiparametric Flow Cytometry Approach

Coppola¹,

Smaldone²,

D’aiuto³

et al. 2022

Cancers

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Immune cell components are able to infiltrate tumor tissues, and different reports described the presence of infiltrating immune cells (TILs) in several types of solid tumors, including breast cancer. The primary immune cell component cells are reported as a lymphocyte population mainly comprising the cytotoxic (CD8+) T cells, with varying proportions of helper (CD4+) T cells and CD19 + B cells, and rarely NK cells. In clinical practice, an expert pathologist commonly detects TILs areas in hematoxylin and eosin (H&E)-stained histological slides via light microscopy. Moreover, other more in-depth approaches could be used to better define the immunological component associated with tumor tissues. Using a multiparametric flow cytometry approach, we have studied the immune cells obtained from breast tumor tissues compared to benign breast pathologies. A detailed evaluation of immune cell components was performed on 15 and 14 biopsies obtained from breast cancer and fibroadenoma subjects, respectively. The percentage of tumor-infiltrating T lymphocytes was significantly higher in breast cancer patients compared to patients with fibroadenoma. Infiltrating helper T lymphocytes were increased in the case of malignant breast lesions, while cytotoxic T lymphocytes disclosed an opposite trend. In addition, our data suggest that the synergistic effect of the presence/activation of NK cells and NKT cells, in line with the data in the literature, determines the dampening of the immune response. Moreover, the lymphocyte-to-monocyte ratio was calculated and was completely altered in patients with breast cancer. Our approach could be a potent prognostic factor to be used in diagnostic/therapeutic purposes for the improvement of breast cancer patients’ management.

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Assessing Tumor-Infiltrating Lymphocytes in Breast Cancer: A Proposal for Combining Immunohistochemistry and Gene Expression Analysis to Refine Scoring

Cited by 19 publications

References 67 publications

Differences in tolerogenic status of NK cells between luminal A type, luminal B type, and triple-negative breast cancer

Differences in tolerogenic status of NK cells between luminal A type, luminal B type, and triple-negative breast cancer

Ultra High-Plex Spatial Proteogenomic Investigation of Giant Cell Glioblastoma Multiforme Immune Infiltrates Reveals Distinct Protein and RNA Expression Profiles

Identification of Immune Cell Components in Breast Tissues by a Multiparametric Flow Cytometry Approach

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