Chemotherapy induces dynamic immune responses in breast cancers that impact treatment outcome

Park, Yeon Hee; Lal, Samir; Lee, Jeong Eon; Choi, Yoon‐La; Wen, Ji; Ram, Sripad; Ding, Ying; Lee, Soo Hyun; Powell, Eric L.; Lee, Se Kyung; Yu, Jong Han; Ching, Keith A.; Nam, Jae‐Yong; Kim, Seok Won; Nam, Seok Jin; Kim, Jiyeon; Cho, Soo Youn; Hwang, Sung Ho; Kim, Yu Jin; Bonato, Vinícius; Fernandez, Diane R.; Deng, Shibing; Wang, Shuoguo; Shin, Hyun-Tae; Kang, Eun‐Suk; Park, Woong-Yang; Rejto, Paul A.; Bienkowska, Jadwiga; Kan, Zhengyan

doi:10.1038/s41467-020-19933-0

Cited by 115 publications

(135 citation statements)

References 61 publications

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“…on June 27, 2021. © 2021 American Association for Cancer cancerdiscovery.aacrjournals.org Downloaded from biopsies, such as in breast cancer, where the tumor immune microenvironment was assessed in samples collected before treatment, after the first cycle of neoadjuvant chemotherapy, and at the time of surgery (296). Interestingly, this longitudinal study revealed that the on-treatment immune response was more predictive of treatment outcome compared with the paired baseline samples (296), supporting the inclusion of these types of dynamic real-time analyses in clinical trials wherever possible.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of the Tumor Microenvironment

2021

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The importance of the tumor microenvironment (TME) in dynamically regulating cancer progression and influencing therapeutic outcome is now widely appreciated, and multiple therapies directed to various components of the TME have been developed in recent years. In this review, we will introduce the key cell types and features of the TME; discuss how these can be therapeutically targeted, with an emphasis on therapies that are under clinical evaluation or have been approved; highlight how the TME is altered by various interventions including standardof-care therapies; and conclude with an overview of the opportunities and potential challenges to consider in the coming years.The TME is defined as the complex and rich multicellular environment in which a tumor develops. The TME typically comprises immune cells, including T and B lymphocytes, tumor-associated macrophages (TAM), dendritic cells (DC), natural killer (NK) cells, neutrophils, and myeloid-derived suppressor cells (MDSC); stromal cells such as cancer-associated fibroblasts (CAF), pericytes, and mesenchymal stromal cells; the extracellular matrix (ECM) and other secreted molecules, such as growth factors, cytokines, chemokines, and extracel-absTRaCT Strategies to therapeutically target the tumor microenvironment (TME) have emerged as a promising approach for cancer treatment in recent years due to the critical roles of the TME in regulating tumor progression and modulating response to standard-of-care therapies. Here, we summarize the current knowledge regarding the most advanced TME-directed therapies, which have either been clinically approved or are currently being evaluated in trials, including immunotherapies, antiangiogenic drugs, and treatments directed against cancer-associated fibroblasts and the extracellular matrix. We also discuss some of the challenges associated with TME therapies, and future perspectives in this evolving field.Significance: This review provides a comprehensive analysis of the current therapies targeting the TME, combining a discussion of the underlying basic biology with clinical evaluation of different therapeutic approaches, and highlighting the challenges and future perspectives.Research.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of the Tumor Microenvironment

2021

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“…Chemotherapy has long been considered immune suppressive; however, there is growing evidence that the e cacy of chemotherapy involves not only cell-intrinsic cytotoxic effects but also relies on the activation of antitumor immune responses (2). Recently, a study con rmed that after neoadjuvant chemotherapy for breast cancer, just one cycle of treatment can induce an immune stimulatory microenvironment and upregulation of in ammatory signatures (44). This nding may explain why the IVIM-DWI parameters follow the same trend in animal experiments and clinical trials.…”

Section: Discussionmentioning

confidence: 91%

Intravoxel Incoherent Motion Diffusion-weighted MR Imaging for Monitoring the Immune Response of Immunogenic Chemotherapy

Yin

et al. 2021

Preprint

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Background: Traditional chemotherapeutic drugs have the potential to increase tumor cell immunogenicity by activating immunogenic cell death (ICD). The accumulation of preclinical and clinical evidence suggests that the success of neoadjuvant chemotherapy, immunogenic chemotherapy depends (at least in part) on their ability to stimulate anti-cancer immune responses. Although the pathological examination is the gold standard for detecting the antitumor immune response, it is invasive and cannot be performed repetitively. Hence, the aim of our study was to evaluate the predictive value of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in the quantitative assessment of conventional chemotherapy-activated immune responses in mouse tumor models and clinics.Methods: A total of 19 subcutaneous tumor-bearing mice were randomly divided into treated and control groups. Both groups had orderly IVIM DWI examinations before and on days 6 and 12 after the administration of cyclophosphamide (CPA) or saline. The expressions of immune-related genes in the tumor were measured by qPCR or detected by immunohistochemical assay. In addition, six patients with breast cancer requiring neoadjuvant chemotherapy also underwent functional MRI examinations. The primary statistical analysis methods were the Wilcoxon test of variance, correlation analysis, and the Kruskal-Wallis H test.Results: The tumoral pseudodiffusion coefficient (D*), the perfusion fraction (f), and the blood flow-related parameter (fD*) of the treatment group showed a trend that significantly decreased on day 6. Then, these values increased on day 12, while they displayed the opposite tendency in the control group. Compared with the control group, a strong induction of the expression of the immune responses in the CPA treatment group was observed on day 12. Additionally, the changes in functional MRI parameters in the six patients with breast cancer after neoadjuvant chemotherapy showed similar trends to those in the tumor-bearing mice in the CPA treatment group.Conclusions: The immune response induced by immunogenic chemotherapy could be effectively evaluated using IVIM-DWI. The D and D* values could be potential, sensitive imaging markers for identifying the antitumor immune response initiated by immunogenic chemotherapy.

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“…Liu et al (2020a) reported the important roles of CTLA4 and PDCD1 in tumorigenesis, tumor immunity, and prognosis in Pan-Cancer. Park et al (2020) showed that CD274 expression on tumor cells was associated with prognosis in BRCA patients. Gheybi et al (2017) disclosed the involvement of CD19 in BRCA's immune response, linked with outcomes of BRCA patients.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of the Immune-Oncology Targets and Immune Infiltrates of N6-Methyladenosine-Related Long Noncoding RNA Regulators in Breast Cancer

Zhang

Shen

Cai

et al. 2021

Front. Cell Dev. Biol.

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Breast cancer (BRCA) has become the highest incidence of cancer due to its heterogeneity. To predict the prognosis of BRCA patients, sensitive biomarkers deserve intensive investigation. Herein, we explored the role of N6-methyladenosine-related long non-coding RNAs (m6A-related lncRNAs) as prognostic biomarkers in BRCA patients acquired from The Cancer Genome Atlas (TCGA; n = 1,089) dataset and RNA sequencing (RNA-seq) data (n = 196). Pearson’s correlation analysis, and univariate and multivariate Cox regression were performed to select m6A-related lncRNAs associated with prognosis. Twelve lncRNAs were identified to construct an m6A-related lncRNA prognostic signature (m6A-LPS) in TCGA training (n = 545) and validation (n = 544) cohorts. Based on the 12 lncRNAs, risk scores were calculated. Then, patients were classified into low- and high-risk groups according to the median value of risk scores. Distinct immune cell infiltration was observed between the two groups. Patients with low-risk score had higher immune score and upregulated expressions of four immune-oncology targets (CTLA4, PDCD1, CD274, and CD19) than patients with high-risk score. On the contrary, the high-risk group was more correlated with overall gene mutations, Wnt/β-catenin signaling, and JAK-STAT signaling pathways. In addition, the stratification analysis verified the ability of m6A-LPS to predict prognosis. Moreover, a nomogram (based on risk score, age, gender, stage, PAM50, T, M, and N stage) was established to evaluate the overall survival (OS) of BRCA patients. Thus, m6A-LPS could serve as a sensitive biomarker in predicting the prognosis of BRCA patients and could exert positive influence in personalized immunotherapy.

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Chemotherapy induces dynamic immune responses in breast cancers that impact treatment outcome

Cited by 115 publications

References 61 publications

Therapeutic Targeting of the Tumor Microenvironment

Therapeutic Targeting of the Tumor Microenvironment

Intravoxel Incoherent Motion Diffusion-weighted MR Imaging for Monitoring the Immune Response of Immunogenic Chemotherapy

Comprehensive Analysis of the Immune-Oncology Targets and Immune Infiltrates of N6-Methyladenosine-Related Long Noncoding RNA Regulators in Breast Cancer

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