CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

Turcotte, Martin; Allard, David; Mittal, Deepak; Barèche, Yacine; Buisseret, Laurence; José, Vinu; Pommey, Sandra; Delisle, Vincent; Loi, Sherene; Joensuu, Heikki; Kellokumpu-Lehtinen, Pirkko-Liisa; Sotiriou, Christos; Smyth, Mark J.; Stagg, John

doi:10.1158/0008-5472.can-17-0707

Cited by 99 publications

(74 citation statements)

References 44 publications

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“…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). Tumors also grow slower in A2BR-deficient mice and mice treated with A2BR antagonists (85)(86)(87).…”

Section: Cd73 and Adenosine Receptor Activity Promotes Immunosuppressionmentioning

confidence: 78%

“…High ATP levels promote DC and macrophage antitumor activity, which adds to the antitumor immunity benefits of blocking CD73 (44). Combining CD73 anti-antibodies or small molecule inhibitors with chemotherapy or targeted therapies [e.g., antibodies against epidermal growth factor receptor (EGFR)] also shows merit in preclinical studies (36,81). BRAF and MEK inhibitors combined with A2AR blockade show significant benefit in controlling melanoma tumor growth and metastasis in mice (42).…”

Section: Preclinical Studies Targeting Cd73 and Adenosine Receptorsmentioning

confidence: 99%

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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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Section: Cd73 and Adenosine Receptor Activity Promotes Immunosuppressionmentioning

confidence: 78%

Section: Preclinical Studies Targeting Cd73 and Adenosine Receptorsmentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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“…There is an increasing amount of literature supporting that anti-tumour immunity of anti-neu mAb can be enhanced with immunomodulatory agents such as CD73 33 , PolyI:C and CpG 34 in the highly immunogenic TUBO transplanted WT BALB/c mice. Our study suggests that the potential and underlying mechanisms of action of these combination therapies have to be elucidated in low immunogenic setting using transgenic BALB/c-NeuT recipient mice in order to complement the results obtained in WT BALB/c mice.…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity of rat-neu+ mouse mammary tumours determines the T cell-dependent therapeutic efficacy of anti-neu monoclonal antibody treatment

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Benonisson

Brouwers

et al. 2020

Sci Rep

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The use of Trastuzumab (Herceptin), a monoclonal antibody (mAb) targeting HER2/neu, results in an increased median survival in Her2 + breast cancer patients. the tumour mutational burden and the presence of tumour infiltrating lymphocytes (TILs) clearly correlate with response to trastuzumab. Here, we investigated if the immunogenicity of the transplantable rat-neu + tumour cell line (tUBo) derived from a BALB/c-NeuT primary tumour is associated with the response to anti-neu mAb therapy. We compared the TUBO tumour outgrowth and tumour infiltrating T cells in isogenic (BALB/c-NeuT) and non-isogenic (WT BALB/c) recipient mice. Furthermore, therapeutic efficacy of anti-neu mAb and the contribution of t cells were examined in both mouse strains. the outgrowth of untreated tumours was significantly better in BALB/c-NeuT than WT BALB/c mice. Moreover, tumour infiltrating T cells were more abundantly present in WT BALB/c than BALB/c-NeuT mice, showing that the TUBO tumour was more immunogenic in WT BALB/c mice. In TUBO tumour bearing WT BALB/c mice, anti-neu mAb therapy resulted in an increase of tumour infiltrating T cells and long-term survival. When T cells were depleted, this strong anti-tumour effect was reduced to an outgrowth delay. In contrast, in TUBO tumour bearing BALB/c-NeuT mice, treatment with anti-neu mAb resulted only in tumour outgrowth delay, both in the presence and absence of t cells. We concluded that in immunogenic tumours the response to anti-neu mAb therapy is enhanced by additional t cell involvement compared to the response to anti-neu mAb in non-immunogenic tumours.Overexpression of oncogenic Her2 protein occurs in 15-20% of breast cancers and is associated with highly aggressive disease. Trastuzumab, a humanized IgG1 monoclonal antibody targeting Her2, is the standard therapy for Human epidermal growth factor receptor 2 (HER2/Erbb2/neu) overexpressing breast cancer owing to its apparent efficacy in adjuvant and neoadjuvant uses 1,2 . This antibody was designed to disrupt the ligand-independent HER2-HER2 interaction resulting in rapid inhibition of pro-survival signalling pathways, leading to cell cycle arrest of the cancer cells 3,4 . The clinical success of Trastuzumab has paved the way for devising novel Her2 targeting approaches in breast cancer treatment. To date, two other therapeutic agents are available to inhibit her2 mediated signalling, a monoclonal antibody (pertuzumab) and tyrosine kinase inhibitors (lapatinib, neratinib). However, a recent clinical study has shown that Trastuzumab therapy increases the pathological complete response (pCR) in patients more than laptinib 5 . This can be attributed to the ability of Trastuzumab to engage the immune system to achieve tumor killing. Several preclinical studies have suggested that innate immune responses are essential to anti-Her2/neu mAb cancer therapies through the recruitment of Fcγ receptor (FcγR) expressing immune cells which can mediate antibody-dependent cellular cytotoxicity (ADCC) 6-8 . This is supported by the observation th...

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“…In vivo studies provide conclusive evidence of the importance of adenosine in cancer (12–15). Abrogation of the adenosine signaling pathway, either through knockdown of the A 2A adenosine receptor (A 2A R), a G-protein coupled receptor (GPCR) expressed in immune cells, or by A 2A R antagonists, reduces tumor burden in tumor-bearing mice, increases survival, and increases the efficacy of immunotherapies (5, 6, 9, 16–18).…”

Section: Introductionmentioning

confidence: 99%

A defect in KCa3.1 channel activity limits the ability of CD8 ⁺ T cells from cancer patients to infiltrate an adenosine-rich microenvironment

et al. 2018

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The limited ability of cytotoxic T cells to infiltrate solid tumors hampers immune surveillance and the efficacy of immunotherapies in cancer. Adenosine accumulates in solid tumors and inhibits tumor-specific T cells. Adenosine inhibits T cell motility through the A2A receptor (A2AR) and suppression of KCa3.1 channels. Herein, we conducted 3-dimensional chemotaxis experiments to elucidate the effect of adenosine on the migration of peripheral blood CD8+ T cells from head and neck squamous cell carcinoma (HNSCC) patients. The chemotaxis of HNSCC CD8+ T cells was reduced in the presence of adenosine, and the effect was greater on HNSCC CD8+ T cells than on healthy donor (HD) CD8+ T cells. This response correlated with the inability of CD8+ T cells to infiltrate tumors. The effect of adenosine was mimicked by an A2AR agonist and prevented by an A2AR antagonist. We found no differences in A2AR expression, cAMP abundance, or protein kinase A1 activity between HNSCC and HD CD8+ T cells. We instead detected a decrease in KCa3.1 channel activity, but not expression, in HNSCC CD8+ T cells. Activation of KCa3.1 channels by 1-EBIO restored the ability of HNSCC CD8+ T cells to chemotax in the presence of adenosine. Our data highlight the mechanism underlying the increased sensitivity of HNSCC CD8+ T cells to adenosine and the potential therapeutic benefit of KCa3.1 channel activators, which could increase infiltration of these T cells into tumors.

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CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

Cited by 99 publications

References 44 publications

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

Immunogenicity of rat-neu+ mouse mammary tumours determines the T cell-dependent therapeutic efficacy of anti-neu monoclonal antibody treatment

A defect in KCa3.1 channel activity limits the ability of CD8 ⁺ T cells from cancer patients to infiltrate an adenosine-rich microenvironment

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CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

Cited by 99 publications

References 44 publications

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

Immunogenicity of rat-neu+ mouse mammary tumours determines the T cell-dependent therapeutic efficacy of anti-neu monoclonal antibody treatment

A defect in KCa3.1 channel activity limits the ability of CD8 + T cells from cancer patients to infiltrate an adenosine-rich microenvironment

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A defect in KCa3.1 channel activity limits the ability of CD8 ⁺ T cells from cancer patients to infiltrate an adenosine-rich microenvironment