Single-cell spatial analysis may help predict response to neoadjuvant immunotherapy in triple-negative breast cancer

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Next-generation technologies that enable the study of protein expression at the single-cell level and the location of cells within the tumor microenvironment (TME) are feasible and the benefits of adding the immune checkpoint inhibitor atezolizumab (Tecentriq). Chemotherapy as neoadjuvant therapy for patients with early-stage, high-risk, locally advanced triple-negative breast cancer (TNBC), according to the results presented in San Antonio Breast Cancer Symposium, Held December 7-10, 2021.

Giampaolo Bianchini, MD, Head of the Breast Cancer Group at the Department of Clinical Oncology at IRCCS Pedales San Raffaele in Milan, said: “Among these, imaging mass cytometry makes it possible to collect unprecedented information about the heterogeneity of the tumor and its surrounding microenvironment.”

Imaging mass cytometry (IMC) allows simultaneous analysis of more than 40 markers in a single tissue section to identify the set of proteins present on it. Individual cellsBianchini explained, explaining the exact location within the organization. IMC combines and analyzes the principles of flow cytometry Single cell Alternatively, mass spectrometry to identify particles that pass through a single or multiple lasers, and molecules present in the sample by accurately measuring the mass.

New evidence shows infiltration of TNBC tumors Mononuclear cell And lymphocytes. The combination of immune checkpoint inhibition and chemotherapy showed significant benefit in high-risk TNBC patients in the KEYNOTE-522 trial and was approved by the FDA for pembrolizumab (Keytruda) in combination with chemotherapy as neoadjuvant therapy in this setting. I was connected.

“Unfortunately, one size may not fit all patients, and some patients may have responded only to chemotherapy, while others who originally benefited from immunotherapy will eventually benefit. It can recur. In addition, although immunotherapy is generally well tolerated, rare but potentially serious immune-related side effects have been reported, “commented Biannini. “For these reasons, to identify patients who will most benefit from the addition of chemotherapy, who may lead to escalation of chemotherapy or a strategy without chemotherapy, and who will be successful with chemotherapy alone. Biomarkers are urgently needed. “

Bianchini et al. Investigated whether IMC could help identify ideal candidates for this therapeutic approach.They performed an IMC analysis in the context of Phase III NeoTRIPaPDL1 The addition of atezolizumab (Tecentriq) to the chemotherapeutic agents carboplatin and nab-paclitaxel (Abraxane) was evaluated as neoadjuvant therapy for early-stage high-risk and locally advanced TNBC patients compared to carboplatin and nab-paclitaxel alone. He underwent surgery within 6 weeks of completing the trial treatment designed to do so.

“We evaluated the predictive value of identifying different phenotypes present in tumors and TMEs through single-cell analysis, and the association of cell-cell interactions,” said group leaders H Raza Ali, MD, and Ph. .D. Says. Cancer Research UK Cambridge Institute and University of Cambridge, and key contributors to this research. “Information on the spatial composition of tumor tissue is important when studying the response to immunotherapy, as both immune activation and tumor cell death require physical interaction between cells.”

Researchers have successfully analyzed 43 proteins expressed in over 1 million single cells. Tissue sample Collected by pretreatment biopsy from 243 patients (equivalent to 86.8 percent of the study population). For each sample, we generated three high-dimensional images containing the tumor, the tumor interstitial interface, and the adjacent stromal. They have a complete pathological response rate defined as the absence of invasive cancer cells in protein expression, cell phenotype, and spatial tissue in tumors and TME cells, and in tissue samples collected during surgery. We investigated the relationship with pCR).

According to the author, bulk protein expression analysis may provide limited predictive information because it does not consider the intracellular compartment in which each protein is expressed. For example, assessment of Ki67 on TME cells and HLA-DR on epithelial cells appeared to provide more predictive information than the same biomarker assessed across tissue specimens.

By being able to accurately identify different cell phenotypes, such as cell type and functional state, this approach reveals a potential predictive role for the density of a particular cell population. It is a high-density antigen-presenting cell and immunosuppressant with high expression of PD-L1. Epithelial cells with high expression of molecular IDO and CD56 neuroendocrine markers were associated with high pCR in patients receiving atezolizumab and chemotherapy, but not in patients receiving chemotherapy alone.

In addition, the high spatial connectivity between epithelial cells and specific TME cells, such as CD8 + T cells with the characteristics of expression and depletion of granzyme B or PD1, is a significant increase in pCR rate after atezolizumab. These decreased expression markers were associated with similar pCR rates between the atezolizumab group and the chemotherapy-only group.

“Our results show that spatial data on TME-specific cell-cell interactions can be very informative about the benefits provided by immune checkpoint inhibitors such as atezolizumab in addition to chemotherapy. “Bianchini commented. “This kind of information can only be provided by technology that allows us to accurately characterize a single cell and its spatial localization at the same time.”

This approach also confirmed the extreme heterogeneity of TNBC in terms of both tumor cell composition and quantity, type, and functional status. cell Exists in TME.

“The predictive information obtained through IMC complemented what can be derived from commonly used immune biomarkers, such as PD-L1 expression and the amount of stromal tumor-infiltrating lymphocytes. In addition, some to capture immunity. Immune-related gene expression signatures were found. The cell type and function were less informative than the corresponding biomarkers assessed by IMC. “

Due to the complexity of IMC technology, it was questioned whether it could be applied to a series of large tumor samples, such as those collected in daily work. “Our research demonstrates that this disruptive technique can be successfully applied to prospectively collected samples in large clinical trials, paving the way for widespread implementation in cancer research to support precision immunology. It opened, “Bianchini added.

According to the author, all discoveries in this study require independent verification. In addition, formal adjustments to multiple comparisons did not apply, so care was taken in interpreting the results. Finally, the reproducibility and applicability of this technology outside the research environment still needs to be investigated.

Studies identify biomarkers for breast cancer response to immunotherapy

For more information:
Summary: GS1-00. Imaging of Triple Negative Breast Cancer (TNBC) in NeoTRIPa PDL1 Trial Single Cell Spatial Analysis by Mass Cytometry and Immunotherapy Response

Quote: Single-cell spatial analysis obtained from https: // 7, 2021 Triple Negative Breast Cancer (December 7, 2021) May help predict response to neoadjuvant immunotherapy in analysis-response-neoadjuvant.html

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