Effector memory cytotoxic CD3+/CD8+/CD45RO+ T cells are predictive of good survival and a lower risk of recurrence in triple-negative breast cancer

Sun, Xin; Zhai, Jie; Sun, Baohua; Parra, Edwin R.; Jiang, Mei; Ma, Wencai; Wang, Jing; Kang, Anthony M; Kannan, Kasthuri; Pandurengan, Renganayaki; Zhang, Shanyu; Solis, Luisa M.; Haymaker, Cara; Raso, Maria Gabriela; Perez, Julia Mendoza; Şahin, Ayşegül; Wistuba, Ignacio I.; Yam, Clinton; Litton, Jennifer K.; Yang, Fei

doi:10.1038/s41379-021-00973-w

Cited by 14 publications

(15 citation statements)

References 45 publications

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“…Many studies have reported that TNBC with a high level of sTILs showed better short-term and long-term prognoses ( 21 – 23 ). The main reason for this was that the CD4+ T cells and CD8+ T cells (primary effector sTIL subtypes) had been linked to a better response to anti-tumor treatment in triple-negative breast cancer ( 24 , 25 ). However, a small number of studies reported that TNBC patients with sTIL enrichment after NAC were at a higher risk of relapse ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Characteristics of recurrence, predictors for relapse and prognosis of rapid relapse triple-negative breast cancer

Cai

Liu²,

Liu³

et al. 2023

Front. Oncol.

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BackgroundTriple-negative breast cancer (TNBC) patients who recur at different times are associated with distinct biological characteristics and prognoses. Research on rapid-relapse TNBC (RR-TNBC) is sparse. In this study, we aimed to describe the characteristics of recurrence, predictors for relapse, and prognosis in rrTNBC patients.MethodsClinicopathological data of 1584 TNBC patients from 2014 to 2016 were retrospectively reviewed. The characteristics of recurrence were compared between patients with RR-TNBC and slow relapse TNBC(SR-TNBC). All TNBC patients were randomly divided into a training set and a validation set to find predictors for rapid relapse. The multivariate logistic regression model was used to analyze the data of the training set. C-index and brier score analysis for predicting rapid relapse in the validation set was used to evaluate the discrimination and accuracy of the multivariate logistic model. Prognostic measurements were analyzed in all TNBC patients.ResultsCompared with SR-TNBC patients, RR-TNBC patients tended to have a higher T staging, N staging, TNM staging, and low expression of stromal tumor-infiltrating lymphocytes (sTILs). The recurring characteristics were prone to appear as distant metastasis at the first relapse. The first metastatic site was apt to visceral metastasis and less likely to have chest wall or regional lymph node metastasis. Six predictors (postmenopausal status, metaplastic breast cancer,≥pT3 staging,≥pN1 staging, sTIL intermediate/high expression, and Her2 [1+]) were used to construct the predictive model of rapid relapse in TNBC patients. The C-index and brier score in the validation set was 0.861 and 0.095, respectively. This suggested that the predictive model had high discrimination and accuracy. The prognostic data for all TNBC patients showed that RR-TNBC patients had the worst prognosis, followed by SR-TNBC patients.ConclusionRR-TNBC patients were associated with unique biological characteristics and worse outcomes compared to non-RR-TNBC patients.

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Section: Discussionmentioning

confidence: 99%

Characteristics of recurrence, predictors for relapse and prognosis of rapid relapse triple-negative breast cancer

Cai

Liu²,

Liu³

et al. 2023

Front. Oncol.

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“…The above in vitro findings demonstrate that IFNg is a key regulator in the induction of NOS2/COX2 expression in ER-breast tumor cells, which raises the question of the origin of IFNg secretion in tumor tissues. Cytotoxic lymphocytes release IFNg and are associated with improved survival in TNBC and other cancer types (19)(20)(21). In contrast, elevated tumor NOS2/COX2 expression promote disease progression and are strongly predictive of poor disease-specific breast cancer survival (7,9,14).…”

Section: Spatial Identification Of Nos2 and Cox2 Nichesmentioning

confidence: 99%

Interferon-gamma is Quintessential for NOS2 and COX2 Expression in ER^-Breast Tumors that Lead to Poor Outcome

Cheng

Ridnourl

Wink

et al. 2023

Preprint

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A strong correlation between NOS2 and COX2 tumor expression and poor clinical outcomes in ER- breast cancer has been established. However, mechanisms of tumor induction of these enzymes are unclear. Analysis of The Cancer Genome Atlas (TCGA) revealed correlations between NOS2 and COX2 expression and Th1 cytokines. Herein, single cell RNAseq analysis of TNBC cells shows potent NOS2 and COX2 induction by IFNg combined with IL1b or TNFa. Given that IFNg is secreted by cytolytic lymphocytes, which improve clinical outcomes, this role of IFNg presents a dichotomy. To explore this conundrum, tumor NOS2, COX2, and CD8+ T cells werespatially analyzed in aggressive ER-, TNBC, and HER2+ breast tumors. High expression and clustering of NOS2-expressing tumor cells occurred at the tumor/stroma interface in the presence of stroma restricted CD8+ T cells. High expression and clustering of COX2-expressing tumor cells extended into immune desert regions in the tumor core where CD8+ T cell penetration was limited or absent. Moreover, high NOS2-expressing tumor cells were proximal to areas with increased satellitosis suggestive of cell clusters with a higher metastatic potential. Further in vitro experiments revealed that IFNg+IL1b/TNFa increased elongation and migration of treated tumor cells. This spatial analysis of the tumor microenvironment provides important insight of distinct neighborhoods where stroma-restricted CD8+ T cells exist proximal to NOS2-expressing tumor niches that could have increased metastatic potential.

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“…Tumors can modify the microenvironment by releasing extracellular molecules, inducing tumor angiogenesis and promoting peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells. Increasing amounts of T CD3 + , cytotoxic CD8 + and memory CD45RO + T cells are associated with greater diseasefree survival and overall survival (OS) in most studies [1][2][3]. Histological analysis of tumors has highlighted the importance of immunological infiltrates, including macrophages, dendritic cells, polymorphonuclear cells, natural killer (NK) cells, B cells and T cells, and revealed a wide diversity of these among patients [4].…”

Section: Introductionmentioning

confidence: 99%

Regulatory cells and the effect of cancer immunotherapy

Iglesias-Escudero

Arias-González²,

Martı́nez-Cáceres

2023

Mol Cancer

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Several mechanisms and cell types are involved in the regulation of the immune response. These include mostly regulatory T cells (Tregs), regulatory macrophages (Mregs), myeloid suppressor cells (MDSCs) and other regulatory cell types such as tolerogenic dendritic cells (tolDCs), regulatory B cells (Bregs), and mesenchymal stem cells (MSCs). These regulatory cells, known for their ability to suppress immune responses, can also suppress the anti-tumor immune response. The infiltration of many regulatory cells into tumor tissues is therefore associated with a poor prognosis. There is growing evidence that elimination of Tregs enhances anti-tumor immune responses. However, the systemic depletion of Treg cells can simultaneously cause deleterious autoimmunity. Furthermore, since regulatory cells are characterized by their high level of expression of immune checkpoints, it is also expected that immune checkpoint inhibitors perform part of their function by blocking these molecules and enhancing the immune response. This indicates that immunotherapy does not only act by activating specific effector T cells but can also directly or indirectly attenuate the suppressive activity of regulatory cells in tumor tissues. This review aims to draw together our current knowledge about the effect of immunotherapy on the various types of regulatory cells, and how these effects may be beneficial in the response to immunotherapy.

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Effector memory cytotoxic CD3+/CD8+/CD45RO+ T cells are predictive of good survival and a lower risk of recurrence in triple-negative breast cancer

Cited by 14 publications

References 45 publications

Characteristics of recurrence, predictors for relapse and prognosis of rapid relapse triple-negative breast cancer

Characteristics of recurrence, predictors for relapse and prognosis of rapid relapse triple-negative breast cancer

Interferon-gamma is Quintessential for NOS2 and COX2 Expression in ER^-Breast Tumors that Lead to Poor Outcome

Regulatory cells and the effect of cancer immunotherapy

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Effector memory cytotoxic CD3+/CD8+/CD45RO+ T cells are predictive of good survival and a lower risk of recurrence in triple-negative breast cancer

Cited by 14 publications

References 45 publications

Characteristics of recurrence, predictors for relapse and prognosis of rapid relapse triple-negative breast cancer

Characteristics of recurrence, predictors for relapse and prognosis of rapid relapse triple-negative breast cancer

Interferon-gamma is Quintessential for NOS2 and COX2 Expression in ER-Breast Tumors that Lead to Poor Outcome

Regulatory cells and the effect of cancer immunotherapy

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Interferon-gamma is Quintessential for NOS2 and COX2 Expression in ER^-Breast Tumors that Lead to Poor Outcome