Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial

Buisseret, Laurence; Pommey, Sandra; Allard, Bertrand; Garaud, Soizic; Bergeron, Marcelle; Cousineau, Isabelle; Ameye, Lieveke; Barèche, Yacine; Paesmans, Marianne; Crown, John; Leo, Angelo Di; Loi, Sherene; Piccart‐Gebhart, Martine; Willard-Gallo, Karen; Sotiriou, Christos; Stagg, John

doi:10.1093/annonc/mdx730

Cited by 166 publications

(144 citation statements)

References 25 publications

(30 reference statements)

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“…Hence, the development of targeted CD73/A2aR adenosine signaling therapies requires the effective stratification of patients to recognize the therapeutic potential of these approaches. In triple‐negative breast cancer, CD73 expression on epithelial tumor cells had a significant negative correlation with CD45 + immune cell infiltration, and patients with high CD73 epithelial expression as well as low CD45 + immune cell infiltration had the worst survival . In our study, we found that DLBCL patients with CD73 positivity on tumor cells as well as low CD8 + immune cell infiltration had the worst survival, and DLBCL patients with CD73 negativity on tumor cells as well as high CD8 + immune cell infiltration had the best clinical outcome.…”

Section: Discussionsupporting

confidence: 46%

“…In triplenegative breast cancer, CD73 expression on epithelial tumor cells had a significant negative correlation with CD45 + immune cell infiltration, and patients with high CD73 epithelial expression as well as low CD45 + immune cell infiltration had the worst survival. 25 In our study, we found that DLBCL patients with CD73 positivity on tumor cells as well as low CD8 + immune cell infiltration had the worst survival, and DLBCL patients with CD73 negativity on tumor cells as well as high CD8 + immune cell infiltration had the best clinical outcome. A similar phenomenon was also observed using the ALCs in the peripheral blood instead of CD8 + immune cell infiltration in tissue.…”

Section: Discussionsupporting

confidence: 46%

See 1 more Smart Citation

Tumor CD73/A2aR adenosine immunosuppressive axis and tumor‐infiltrating lymphocytes in diffuse large B‐cell lymphoma: correlations with clinicopathological characteristics and clinical outcome

Zhang

Zheng

et al. 2019

Intl Journal of Cancer

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Novel immune checkpoint blockades, including those targeting CD73 and A2aR, are being evaluated in malignancies in clinical trials. Here, we investigated the expression of CD73 and A2aR as well as tumor‐infiltrating lymphocytes (TILs), and analyzed their correlations with clinicopathological characteristics and survival in diffuse large B‐cell lymphoma (DLBCL). We found that CD73 expression on tumor cells, rather than the total protein and gene levels of CD73, was associated with survival. Patients with CD73+/Pax‐5+ (median survival, 57.8 months; 95% CI, 46.4–69.3) experienced significantly poorer outcomes than those with CD73−/Pax‐5+ (median survival, 73.5 months; 95% CI, 65.9–81.2). Additionally, A2aR expression on both total TILs and CD8+ TILs was correlated with survival. Patients with A2aR+ TILs (median survival, 53.3 months; 95% CI, 40.6–66.0) had a significantly shorter survival time than patients with A2aR− TILs (median survival, 74.5 months; 95% CI, 67.5–81.5). Spearman's rank test showed that CD73 expression on tumor cells was positively correlated with A2aR expression on TILs (R = 0.395, p = 0.001). We further found that patients could be more precisely stratified through the combination of CD73 tumor cell expression and A2aR TILs expression, and patients with CD73+/Pax‐5+ and A2aR+ TILs experienced the worst outcome. We also revealed that patients with CD73+/Pax‐5+ and low CD8+ TILs or low absolute lymphocyte counts had unfavorable outcomes. Overall, our findings uncovered that patients with CD73+ on tumor cells as well as A2aR+ on TILs or low CD8+ TILs exhibited inferior survival, supporting potential combination strategies using CD73/A2aR immunosuppressive blockades as treatment options for DLBCL patients.

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Section: Discussionsupporting

confidence: 46%

Section: Discussionsupporting

confidence: 46%

Tumor CD73/A2aR adenosine immunosuppressive axis and tumor‐infiltrating lymphocytes in diffuse large B‐cell lymphoma: correlations with clinicopathological characteristics and clinical outcome

Zhang

Zheng

et al. 2019

Intl Journal of Cancer

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“…These mice also benefit from increased chemotherapy sensitivity (36,71) and reduced angiogenesis (71,72). In line with these studies, many human tumors overexpress CD73 and associates with poor prognosis (36,(73)(74)(75)(76)(77)(78). CD73 is also linked to drug resistance, epithelial-to-mesenchymal transition (EMT), and cancer cell proliferation and stemness (76,(79)(80)(81)(82)(83)(84).…”

Section: Cd73 and Adenosine Receptor Activity Promotes Immunosuppressionmentioning

confidence: 78%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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CD73, a cell surface 5 ′ nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.

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“…This has now been confirmed in human patients as data from the BIG-02-98 study conclude that high levels of CD73 expression on epithelial tumor cells positively associates with reduced DMFS and OS and negatively correlates with tumor immune cell infiltration (Spearman's r = -0.50, P < 0.0001). Patients with high levels of CD73 and low levels of tumorinfiltrating leukocytes had the worse clinical outcome [34] . This suggests that adenosine signaling in TNBC associates with poor patient survival and that targeting CD73 or A2BR may provide a Overall survival (OS) and distant metastasis free survival (DMSF) were compared and median survival calculated using km plotter.…”

Section: Adenosine Receptor 2b Functioning In Tnbcmentioning

confidence: 99%

Targeting adenosine receptor 2B in triple negative breast cancer

Neumann¹,

Levine²,

Oesterreich³

2018

JCMT

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In the review "Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target", Sorrentino and Morello make a compelling case for considering adenosine 2B receptor (A2BR) as a target in cancer therapy (J Cancer Metastasis Treat 2017;3:127-38). A large body of evidence has accumulated suggesting A2BR to play an active role in tumor immune suppression and metastasis. Thus, this commentary will discuss the intriguing possibility of targeting A2BR in specific breast cancers that express high levels of A2BR and attract infiltrating immune cells. TRIPLE NEGATIVE BREAST CANCER IS SUSCEPTIVE TO IMMUNE MODULATIONTriple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that disproportionally affects younger women and those of African origins, compared with Caucasians [1,2] . TNBC is devoid of the three receptors that classify and define most mammary cancers: estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) [3] . The lack of these receptors reduces the efficacy of targeted therapies for this cancer type, limiting treatment options to chemotherapeutic agents, ionizing radiation and surgery. TNBC patients are therefore in dire need for novel targeted therapies.Breast cancer has long been thought of as a non-immunogenic malignancy. However, a growing body of evidence suggests that this is not the case for all breast cancers. Tumor-infiltrating lymphocytes (TILs) are the most widely studied immune cells and include T cells and B cells. TILs are part of a larger category of infiltrating immune cells that include natural killer (NK) cells, macrophages, neutrophils, dendritic cells,

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Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial

Abstract: Taken together, our study provides further support that CD73 expression is associated with a poor prognosis and reduced anti-tumor immunity in human TNBC and that targeting CD73 could be a promising strategy to reprogram the tumor microenvironment in this BC subtype.

Cited by 166 publications

References 25 publications

Tumor CD73/A2aR adenosine immunosuppressive axis and tumor‐infiltrating lymphocytes in diffuse large B‐cell lymphoma: correlations with clinicopathological characteristics and clinical outcome

Tumor CD73/A2aR adenosine immunosuppressive axis and tumor‐infiltrating lymphocytes in diffuse large B‐cell lymphoma: correlations with clinicopathological characteristics and clinical outcome

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

Targeting adenosine receptor 2B in triple negative breast cancer

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