CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer

Michaels, Alex D.; Newhook, Timothy E.; Adair, Sara J.; Morioka, Sho; Goudreau, Bernadette J.; Nagdas, Sarbajeet; Mullen, Matthew G.; Persily, Jesse; Bullock, Timothy N. J.; Slingluff, Craig L.; Ravichandran, Kodi S.; Parsons, John T.; Bauer, Todd W.

doi:10.1158/1078-0432.ccr-17-2283

Cited by 79 publications

(82 citation statements)

References 41 publications

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“…In fact, CD47 protein expression was significantly high in ovarian cancer and associated with patient stage, chemotherapy resistance, and prognosis. Similar results have been observed in glioma cells, breast cancer cells (147), not small-cells lung carcinoma (NSCLC), PDAC, and others (147)(148)(149)(150). The presence of CD47 in AML was also associated with a high self-renewal potential of cancer stem cells and with low patient survival (151,152).…”

Section: Impaired Dcs Recruitment: Ccl4 Inhibitionsupporting

confidence: 75%

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

et al. 2019

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WNT/β-catenin signaling is involved in many physiological processes. Its implication in embryonic development, cell migration, and polarization has been shown. Nevertheless, alterations in this signaling have also been related with pathological events such as sustaining and proliferating the cancer stem cell (CSC) subset present in the tumor bulk. Related with this, WNT signaling has been associated with the maintenance, expansion, and epithelial-mesenchymal transition of stem cells, and furthermore with two distinctive features of this tumor population: therapeutic resistance (MDR, multidrug resistance) and immune escape. These mechanisms are developed and maintained by WNT activation through the transcriptional control of the genes involved in such processes. This review focuses on the description of the best known WNT pathways and the molecules involved in them. Special attention is given to the WNT cascade proteins deregulated in tumors, which have a decisive role in tumor survival. Some of these proteins function as extrusion pumps that, in the course of chemotherapy, expel the drugs from the cells; others help the tumoral cells hide from the immune effector mechanisms. Among the WNT targets involved in drug resistance, the drug extrusion pump MDR-1 (P-GP, ABCB1) and the cell adhesion molecules from the CD44 family are highlighted. The chemokine CCL4 and the immune checkpoint proteins CD47 and PD-L1 are included in the list of WNT target molecules with a role in immunity escape. This pathway should be a main target in cancer therapy as WNT signaling activation is essential for tumor progression and survival, even in the presence of the anti-tumoral immune response and/or antineoplastic drugs. The appropriate design and combination of anti-tumoral strategies, based on the modulation of WNT mediators and/or protein targets, could negatively affect the growth of tumoral cells, improving the efficacy of these types of therapies.

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Section: Impaired Dcs Recruitment: Ccl4 Inhibitionsupporting

confidence: 75%

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

et al. 2019

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“…A minority of human PDA samples with baseline PD‐L1 upregulation were also seen to have downregulation of MHC class I [75]. Hypoxia also stimulated CD47 expression in PDA, which is a co‐stimulatory molecule that blocks pro‐phagocytic signals in myeloid derived suppressor cells (MDSCs) and macrophages [76,77]. Tumor cells also increase CD39 and CD73 in response to hypoxia, which promotes extracellular adenosine accumulation and can lead to T cell apoptosis [78,79].…”

Section: Hypoxia Promotes Tumorigenesis In Carcinoma Cellsmentioning

confidence: 99%

Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma

Daniel

Sullivan

Labadie

et al. 2019

Clinical & Translational Med

165

109

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Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with limited response to cytotoxic chemoradiotherapy, as well as newer immunotherapies. The PDA tumor microenvironment contains infiltrating immune cells including cytotoxic T cells; however, there is an overall immunosuppressive milieu. Hypoxia is a known element of the solid tumor microenvironment and may promote tumor survival. Through various mechanisms including, but not limited to, those mediated by HIF-1α, hypoxia also leads to increased tumor proliferation and metabolic changes. Furthermore, epithelial to mesenchymal transition is promoted through several pathways, including NOTCH and c-MET, regulated by hypoxia. Hypoxia-promoted changes also contribute to the immunosuppressive phenotype seen in many different cell types within the microenvironment and thereby may inhibit an effective immune system response to PDA. Pancreatic stellate cells (PSCs) and myofibroblasts appear to contribute to the recruitment of myeloid derived suppressor cells (MDSCs) and B cells in PDA via cytokines increased due to hypoxia. PSCs also increase collagen secretion in response to HIF-1α, which promotes a fibrotic stroma that alters T cell homing and migration. In hypoxic environments, B cells contribute to cytotoxic T cell exhaustion and produce chemokines to attract more immunosuppressive regulatory T cells. MDSCs inhibit T cell metabolism by hoarding key amino acids, modulate T cell homing by cleaving L-selectin, and prevent T cell activation by increasing PD-L1 expression. Immunosuppressive M2 phenotype macrophages promote T cell anergy via increased nitric oxide (NO) and decreased arginine in hypoxia. Increased numbers of regulatory T cells are seen in hypoxia which prevent effector T cell activation through cytokine production and increased CTLA-4. Effective immunotherapy for pancreatic adenocarcinoma and other solid tumors will need to help counteract the immunosuppressive nature of hypoxia-induced changes in the tumor microenvironment. Promising studies will look at combination therapies involving checkpoint inhibitors, chemokine inhibitors, and possible targeting of hypoxia. While no model is perfect, assuring that models incorporate the effects of hypoxia on cancer cells, stromal cells, and effector immune cells will be crucial in developing successful therapies.

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“…S1), density of surface markers was measured as the ratio between MFI and forward scatter squared (FSC 2 ; ref. 30).…”

Section: Phenotypic Analyses Of Cll Cellsmentioning

confidence: 99%

Ibrutinib Therapy Releases Leukemic Surface IgM from Antigen Drive in Chronic Lymphocytic Leukemia Patients

Drennan

Chiodin

D’Avola

et al. 2019

Clinical Cancer Research

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Purpose: In chronic lymphocytic leukemia (CLL), disease progression associates with surface IgM (sIgM) levels and signaling capacity. These are variably downmodulated in vivo and recover in vitro, suggesting a reversible influence of tissuelocated antigen. Therapeutic targeting of sIgM function via ibrutinib, an inhibitor of Bruton tyrosine kinase (BTK), causes inhibition and tumor cell redistribution into the blood, with significant clinical benefit. Circulating CLL cells persist in an inhibited state, offering a tool to investigate the effects of drug on BTK-inhibited sIgM.Experimental Design: We investigated the consequences of ibrutinib therapy on levels and function of sIgM in circulating leukemic cells of patients with CLL.Results: At week 1, there was a significant increase of sIgM expression (64% increase from pretherapy) on CLL cells either recently released from tissue or persisting in blood. In contrast, surface IgD (sIgD) and a range of other receptors did not change. SIgM levels remained higher than pretherapy in the following 3 months despite gradual cell size reduction and ongoing autophagy and apoptotic activity. Conversely, IgD and other receptors did not increase and gradually declined. Recovered sIgM was fully N-glycosylated, another feature of escape from antigen, and expression did not increase further during culture in vitro. The sIgM was fully capable of mediating phosphorylation of SYK, which lies upstream of BTK in the Bcell receptor pathway.Conclusions: This specific IgM increase in patients underpins the key role of tissue-based engagement with antigen in CLL, confirms the inhibitory action of ibrutinib, and reveals dynamic adaptability of CLL cells to precision monotherapy. Figure 2.Surface expression of receptors on CLL cells during the first 3 months of ibrutinib therapy. PBMCs were taken at pre-, week 1, month 1, or month 3 of ibrutinib therapy and analyzed for cell surface marker expression taking into account CLL cell size. For each marker, the test MFI was divided by FSC 2 . Pretherapy values were normalized to one (white bar). Each bar represents mean with SEM. The statistical significance of difference was analyzed using the Wilcoxon signed rank test of the FSC-adjusted MFI values. Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P 0.001. Drennan et al.

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CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer

Cited by 79 publications

References 41 publications

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma

Ibrutinib Therapy Releases Leukemic Surface IgM from Antigen Drive in Chronic Lymphocytic Leukemia Patients

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