Cancer immunotherapy based on immune-checkpoint inhibition or adoptive cell therapy has revolutionized cancer care. Nevertheless, a large proportion of patients do not benefit from such treatments. ...Over the past decade, remarkable progress has been made in the development of 'next-generation' therapeutics in immuno-oncology, with inhibitors of extracellular adenosine (eADO) signalling constituting an expanding class of agents. Induced by tissue hypoxia, inflammation, tissue repair and specific oncogenic pathways, the adenosinergic axis is a broadly immunosuppressive pathway that regulates both innate and adaptive immune responses. Inhibition of eADO-generating enzymes and/or eADO receptors can promote antitumour immunity through multiple mechanisms, including enhancement of T cell and natural killer cell function, suppression of the pro-tumourigenic effects of myeloid cells and other immunoregulatory cells, and promotion of antigen presentation. With several clinical trials currently evaluating inhibitors of the eADO pathway in patients with cancer, we herein review the pathophysiological function of eADO with a focus on effects on antitumour immunity. We also discuss the treatment opportunities, potential limitations and biomarker-based strategies related to adenosine-targeted therapy in oncology.
Immune checkpoint blockade has not yet been effective in patients with mismatch repair proficient metastatic colorectal cancer. Targeting immunosuppressive metabolic pathways is being explored as a ...new immunotherapeutic approach. We assessed whether CD73, the rate limiting enzyme that catalyzes the degradation of extracellular AMP into immunosuppressive adenosine, could be an immunological determinant of colorectal liver metastases (CRLMs). By immunofluorescence on tissue microarrays, intratumoral CD73 expression (tCD73) was analyzed in 391 CRLMs resected in 215 patients, and soluble CD73 (sCD73) was measured by ELISA in the pre-operative serum of 193 patients. High tCD73 was associated with worse pathological features, such as multiple and larger CRLMs, and poorer pathologic response to pre-operative chemotherapy. The median time to recurrence and disease-specific survival after CRLM resection was significantly shorter in patients with high tCD73 (11.0 and 46.4 months, respectively) compared with low tCD73 (19.0 and 61.5 months, respectively). tCD73 was strongly associated with patient outcomes independently of clinicopathological variables. sCD73 did not correlate with tCD73. Patients with high levels of sCD73 also had shorter disease-specific survival. Our results suggested that CD73 in CRLMs may be prognostically informative and may help select patients more likely to respond to adenosine pathway blocking agents.
The ecto-nucleotidase CD73 is an important immune checkpoint in tumor immunity that cooperates with CD39 to hydrolyze pro-inflammatory extracellular ATP into immunosuppressive adenosine. While the ...role of CD73 in immune evasion of solid cancers is well established, its role in leukemia remains unclear. To investigate the role of CD73 in the pathogenesis of chronic lymphocytic leukemia (CLL), Eµ-TCL1 transgenic mice that spontaneously develop CLL were crossed with CD73−/− mice. Disease progression in peripheral blood and spleen, and CLL markers were evaluated by flow cytometry and survival was compared to CD73-proficient Eµ-TCL1 transgenic mice. We observed that CD73 deficiency significantly delayed CLL progression and prolonged survival in Eµ-TCL1 transgenic mice, and was associated with increased accumulation of IFN-γ+ T cells and effector-memory CD8+ T cells. Neutralizing IFN-γ abrogated the survival advantage of CD73-deficient Eµ-TCL1 mice. Intriguingly, the beneficial effects of CD73 deletion were restricted to male mice. In females, CD73 deficiency was uniquely associated with the upregulation of CD39 in normal lymphocytes and sustained high PD-L1 expression on CLL cells. In vitro studies revealed that adenosine signaling via the A2a receptor enhanced PD-L1 expression on Eµ-TCL1-derived CLL cells, and a genomic analysis of human CLL samples found that PD-L1 correlated with adenosine signaling. Our study, thus, identified CD73 as a pro-leukemic immune checkpoint in CLL and uncovered a previously unknown sex bias for the CD73-adenosine pathway.
Diabetes mellitus has been on a continual rise as one of the top chronic diseases to affect individuals worldwide. The goal of this study was to determine how exposure from a well-known toxicant, a ...polycyclic aromatic hydrocarbon called 2-aminoanthracene (2AA), could potentially lead to diabetes, damage the liver, and have negative effects to the offspring. Humans are exposed to 2AA from foods cooked in high heat and tobacco smoke, among others. To analyze the effects of 2AA, three groups of Sprague Dawley dams consumed an adulterated 2AA diet from gestation to their postnatal period. Timed-pregnant dams ingested 0 mg/kg (control group (C)), 50 mg/kg (low dose group (LD)), and 100 mg/kg (high dose group (HD)) 2AA. Hepatic gene expressions of Adam8, Bax, Ccng1, CD68, CD93, Cdkn1c, and Ddit4 indicated a significant overexpression of Bax, Ccng1, CD68, CD93, and Cdkn1c in treated groups. Although there was no significant difference in the damage to the liver architecture by 2AA, the positively stained CD68+ cells were slightly increased in treated rats. Significant decreases in the albumin and aspartate aminotransferase levels might indicate an inflammatory response from 2AA exposure in dams. Immunoglobulin A (IgA) concentration was also decreased, in contrast to studies of liver cirrhosis that reported increased serum IgA concentration. Overexpression of genes Ddit4, Cdkn1c, Ccng1, Bax, CD93, and CD68 point to hepatic inflammation and apoptosis. Overall results suggest a link between environmental 2AA exposure and adverse liver effects, which has potential to increase susceptibility to type 2 diabetes and other diseases.
In response to oncogenic threats, tumor suppressor mechanisms that halt cell-cycle progression can stimulate immune-mediated destruction of pre-malignant and malignant cells. Accordingly, defining ...the molecular interactions between tumor suppressor pathways and cancer immunity may be instrumental in the development of novel cancer therapies. We here discuss the immunological consequences of cellular senescence and apoptosis in the context of tumorigenesis. We then review the literature on potential 'danger signals' that may link tumorigenesis and cancer immunosurveillance and discuss the range of immune-regulatory mechanisms that restrict cancer immunity. Finally, we discuss how a better understanding of the interacting pathways governing cell death, danger, and immunity may lead to the development of effective cancer immunotherapies. We propose that the minimum requirements for the induction of clinically relevant immune responses include, on the one hand, the development of therapeutic drugs that can either bypass or rescue intrinsic tumor suppressor pathways while inducing a pro-immunogenic form of cell death and, on the other hand, the concerted combination of immune-stimulatory agents able to enhance tumor-antigen presentation and overcome critical immune-regulatory checkpoints that restrict cancer immunity.
Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few exceptions, their identities remain largely unknown. Here, we profiled tumor and T cells from tumor ...and ascites of patients with high-grade serous carcinoma (HGSC) to uncover the metabolomes of these distinct TME compartments. Cells within the ascites and tumor had pervasive metabolite differences, with a notable enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared with ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide
-methyltransferase, the enzyme that catalyzes the transfer of a methyl group from
-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. Functionally, MNA induces T cells to secrete the tumor-promoting cytokine tumor necrosis factor alpha. Thus, TME-derived MNA contributes to the immune modulation of T cells and represents a potential immunotherapy target to treat human cancer.
The observation that galectin-7 (gal-7) is specifically expressed in mammary myoepithelial (basal) cells prompted us to investigate whether this protein is expressed in the basal cells of other ...tissues. Given that breast and prostate cancer have remarkable underlying biological similarities and given the important roles of basal cells in prostate cancer, we examined the expression patterns and role of gal-7 in human prostate cancer. Using tissue microarray, we found that although gal-7 is readily expressed in basal cells in normal prostate tissue, it is downregulated in prostate cancer (PCa) cells. De novo expression of gal-7 in prostate cancer cells increases their sensitivity to apoptosis in response to etoposide and cisplatin. The assessment of a carbohydrate-recognition domain (CRD)-defective mutant form of gal-7 (R7S) showed that the ability of this protein to modulate apoptosis was independent of its CRD activity. This activity was also independent of its ability to translocate to the mitochondrial and nuclear compartments. However, CRD activity was necessary to inhibit the invasive behaviors of prostate cancer cells. In vivo, gal-7 overexpression in PCa cells led to a modest yet significant reduction in tumor size, while its CRD-defective mutant form significantly increased tumor growth compared to controls. Taken together, these results suggest that although de novo expression of gal-7 may be an interesting means of increasing the tumorigenic phenotypes of PCa cells, alterations in the CRD activity of this protein drive a phenotypic switch in its role in PCa cells. This CRD-independent activity represents a paradigm shift in our understanding of the functions of galectin. The R74S model will be useful to distinguish CRD-dependent and CRD-independent functions of gal-7 in cancer progression.
Milk fat globule-epidermal growth factor-8 (MFG-E8) is a glycoprotein secreted by different cell types, including apoptotic cells and activated macrophages. MFG-E8 is highly expressed in a variety of ...cancers and is classically associated with tumor growth and poor patient prognosis through reprogramming of macrophages into the pro-tumoral/pro-angiogenic M2 phenotype. To date, correlations between levels of MFG-E8 and patient survival in prostate and renal cancers remain unclear. Here, we quantified MFG-E8 and CD68/CD206 expression by immunofluorescence staining in tissue microarrays constructed from renal (
= 190) and prostate (
= 274) cancer patient specimens. Percentages of MFG-E8-positive surface area were assessed in each patient core and Kaplan-Meier analyses were performed accordingly. We found that MFG-E8 was expressed more abundantly in malignant regions of prostate tissue and papillary renal cell carcinoma but was also increased in the normal adjacent regions in clear cell renal carcinoma. In addition, M2 tumor-associated macrophage staining was increased in the normal adjacent tissues compared to the malignant areas in renal cancer patients. Overall, high tissue expression of MFG-E8 was associated with less disease progression and better survival in prostate and renal cancer patients. Our observations provide new insights into tumoral MFG-E8 content and macrophage reprogramming in cancer.
Background: WNT1-Inducible Signaling Pathway Protein 1 (WISP1) is implicated in prostate cancer growth and metastasis and the regulation of inflammation in diverse benign diseases. The objectives of ...this study were to assess the prognostic value of WISP1, its association to inflammation and its relevance as a biomarker for immune checkpoint blockade (ICB) response.
Methods: Publicly available RNA-seq datasets were used to evaluate the prognostic value of WISP1 gene expression and its association with tumor-infiltrating lymphocytes, inflamed tumor microenvironment, and anti-PD-1 ICB response. A tissue microarray (TMA) including 285 radical prostatectomy specimens was used to confirm these associations in prostate cancer. The effect of recombinant WISP1 (rWISP1) on inflammatory cytokines was assessed in vitro.
Results: High levels of WISP1 correlated with BCR-free survival in prostate adenocarcinoma and overall survival in primary melanoma, low-grade glioma, and kidney papillary cell carcinoma. Some effects could be accounted for by higher WISP1 expression in advanced disease. High WISP1 expression in prostate adenocarcinoma was correlated with CD8+ cells density. In vitro, rWISP1 increased inflammatory cytokine production. High WISP1 gene expression in RNA-seq datasets was correlated with gene signatures of multiple immune cell types as well as an inflammatory cytokine, immune checkpoint, and epithelial-mesenchymal transition (EMT) gene expression. WISP1 mRNA expression was associated with primary resistance to ICB in datasets showing EMT.
Conclusions: Our results support an association between WISP1 expression and advanced disease, EMT and an inflamed tumor microenvironment in multiple solid tumors. The consequences of WISP1 expression on cancer immunotherapy remains to be addressed.
Targeting A2 adenosine receptors in cancer Allard, David; Turcotte, Martin; Stagg, John
Immunology and cell biology,
April 2017, Letnik:
95, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Tumor cells use various ways to evade anti-tumor immune responses. Adenosine, a potent immunosuppressive metabolite, is often found elevated in the extracellular tumor microenvironment. Therefore, ...targeting adenosine-generating enzymes (CD39 and CD73) or adenosine receptors has emerged as a novel means to stimulate anti-tumor immunity. In particular, the A2 (A2a and A2b) adenosine receptors exhibit similar immunosuppressive and pro-angiogenic functions, yet have distinct biological roles in cancer. In this review, we describe the common and distinct biological consequences of A2a and A2b adenosine receptor signaling in cancer. We discuss recent pre-clinical studies and summarize the different mechanisms-of-action of adenosine-targeting drugs. We also review the rationale for combining inhibitors of the adenosine pathway with other anticancer therapies such immune checkpoint inhibitors, tumor vaccines, chemotherapy and adoptive T cell therapy.
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