Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy

The cell surface enzyme CD73 is increasingly appreciated as a pivotal non-redundant immune checkpoint (IC) in addition to PD-1/PD-L1 and CTLA-4. CD73 produces extracellular adenosine (eADO), which not only inhibits antitumor T cell activity via the adenosine receptor (AR) A2AR, but also enhances the immune inhibitory function of cancer-associated fibroblasts and myeloid cells via A2BR. Preclinical studies show that inhibition of the CD73-adenosinergic pathway in experimental models of many solid tumors either as a monotherapy or, more effectively, in combination with PD-1/PD-L1 or CTLA-4 IC blockades, improves antitumor immunity and tumor control. Consequently, approximately 50 ongoing phase I/II clinical trials targeting the CD73-adenosinergic IC are currently listed on https://clinicaltrials.gov. Most of the listed trials employ CD73 inhibitors or anti-CD73 antibodies alone, in combination with A2AR antagonists, and/or with PD-1/PD-L1 blockade. Recent evidence suggests that the distribution of CD73, A2AR and A2BR in tumor microenvironments (TME) is heterogeneous, and this distribution affects CD73-adenosinergic IC function. The new insights have implications for the optimally effective, carefully tailored approaches to therapeutic targeting of this essential IC. In the mini-review, we briefly discuss the cellular and molecular mechanisms of CD73/eADO-mediated immunosuppression during tumor progression and therapy in the spatial context of the TME. We include preclinical data regarding therapeutic CD73-eADO blockade in tumor models as well as available clinical data from completed trials that targeted CD73-adenosinergic IC with or without PD-1/PD-L1 inhibitors and discuss factors that are potentially important for optimal therapeutic outcomes in cancer patients

Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model

WOS: 000462721900029PubMed ID: 30926774Although clinically apparent metastasis is associated with late stages of cancer development, micro-metastatic dissemination may be an early event. However, the fate of these early disseminated tumor cells (DTC) remains elusive. We show that despite their capacity to disseminate into secondary organs, 4T1 tumor models develop overt metastasis while EMT6-tumor bearing mice clear DTCs shed from primary tumors as well as those introduced by intravenous (IV) injection. Following the surgical resection of primary EMT6 tumors, mice do not develop detectable metastasis and reject IV-injected tumor cells. In contrast, these cells readily grow and metastasize in immuno-deficient athymic or Rag2(-/- )mice, an effect mimicked by CD8(+) T-cell depletion in immunocompetent mice. Furthermore, recombinant G-CSF or adoptive transfer of granulocytic-MDSCs isolated from 4T1 tumor-bearing mice, induce metastasis by suppressing CD8(+) T-cells in EMT6-primed mice. Our studies support the concept of immune surveillance providing molecular insights into the immune mechanisms during tumor progression.Georgia Cancer Center; Forbes Institute research fund; Bridge Fund by Augusta University Research Inc.; American Cancer Society Institutional fundWe gratefully acknowledge the generous help from Flow Cytometry, Genomics Core facilities, and Labaratory of Animal Services. We thank Drs. Rafi Ahmed and Paulo C. Rodriguez for insightful discussions and comments, Dr. Iskander Asm for for helping with and training of our staff on the tail vein injections. This work was supported by start up funds to H.K. by Georgia Cancer Center. Additional research fundings to H.K. provided by American Cancer Society Institutional fund, Forbes Institute research fund, and Bridge Fund by Augusta University Research Inc

Mitochondrial reprogramming by activating OXPHOS via glutamine metabolism in African American patients with bladder cancer

Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy

The Helicobacter pylori Genome Project : insights into H. pylori population structure from analysis of a worldwide collection of complete genomes

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics

Wherefore Art Thou, YY1?

In this issue, Taguchi et al. demonstrate that the transcription factor Yin Yang-1 (YY1) regulates proliferation in three-dimensional cultures of the HaCaT human keratinocyte cell line. HaCaT keratinocytes overexpressing YY1 form artificial epidermal constructs that are thicker than those produced from vector-transfected cells. RNA interference-mediated YY1 knockdown decreases the thickness of YY1-overexpressing constructs, indicating that YY1 mediates the thickening. In primary keratinocytes, overexpressed YY1 also inhibits differentiation marker expression induced by calcium, supporting the idea that YY1 is important in regulating epidermal structure and function

Immune subtraction for improved resolution in serum protein immunofixation electrophoresis and antibody isotype determination in a patient with autoantibody

Heavy chain isotypes of low level monoclonal immunoglobulins are sometimes obscured in serum immunofixation electrophoresis (SIFE) by a heavy background of polyclonal immunoglobulins. However, accurate determination of the heavy chain isotype is essential for a complete diagnosis, as isotype determination of autoantibodies may have relevance in determining therapeutic procedures. Immune subtraction (IS) was employed in a patient with neuropathy and GD1a autoantibody. IS allowed identification of the cognate heavy chain related to a lambda light chain restriction noted on initial SIFE as well as isotype determination of the autoantibody.Antisera specific to individual heavy and light chains were used for depletion of specific immunoglobulin types. Depletion of kappa light chain associated immunoglobulins allowed unequivocal determination of the isotype of lambda light chain-associated low level monoclonal band to be IgG Lambda. Selective depletion of kappa, lambda, gamma and mu heavy chain immunoglobulins was employed to determine IgG Kappa isotype of the auto-antibody