C reactive protein impairs adaptive immunity in immune cells of patients with melanoma.

BACKGROUND: High C reactive protein (CRP) levels have been reported to be associated with a poor clinical outcome in a number of malignancies and with programmed cell death protein 1 immune checkpoint blockade in patients with advanced cancer. Little is known about the direct effects of CRP on adaptive immunity in cancer. Therefore, we investigated how CRP impacted the function of T cells and dendritic cells (DCs) from patients with melanoma. METHODS: The effects of CRP on proliferation, function, gene expression and phenotype of patient T cells and DCs, and expansion of MART-1 antigen-specific T cells were analyzed by multicolor flow cytometry and RNA-seq. Additionally, serum CRP levels at baseline from patients with metastatic melanoma treated on the Checkmate-064 clinical trial were assessed by a Luminex assay. RESULTS: In vitro, CRP inhibited proliferation, activation-associated phenotypes and the effector function of activated CD4+ and CD8+ T cells from patients with melanoma. CRP-treated T cells expressed high levels of interleukin-1ß, which is known to enhance CRP production from the liver. CRP also suppressed formation of the immune synapse and inhibited early events in T-cell receptor engagement. In addition, CRP downregulated the expression of costimulatory molecules on mature DCs and suppressed expansion of MART-1-specific CD8+ T cells in a dose-dependent manner by impacting on both T cells and antigen-presenting cells. High-serum CRP levels at baseline were significantly associated with a shorter survival in both nivolumab-treated and ipilimumab-treated patients. CONCLUSIONS: These findings suggest that high levels of CRP induce an immunosuppressive milieu in melanoma and support the blockade of CRP as a therapeutic strategy to enhance immune checkpoint therapies in cancer. TRIAL REGISTRATION NUMBER: NCT01783938 and NCT02983006.

Novel Checkpoints and Cosignaling Molecules in Cancer Immunotherapy.

The recent demonstration of the antitumor efficacy of checkpoint protein inhibition has resulted in the approval of blocking antibodies against the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway in multiple different histologic findings. Therapeutic successes with PD-1/PD-L1 antibodies in melanoma and lung cancer have been followed by approvals in bladder, renal, and head and neck cancers and Hodgkin lymphoma, with others undoubtedly to come. However, PD-1 is only one of many checkpoints and agonistic regulatory molecules expressed on T cells by which maintenance of the balance between costimulatory and coinhibitory signaling pathways is perturbed in cancer. The manipulation of many of these molecules in cancer patients might be associated with clinical benefit. The majority of the T-cell cosignaling receptors belong to either the immunoglobulin superfamily or the tumor necrosis factor receptor superfamily. A total of 29 immunoglobulin superfamily and 26 tumor necrosis factor receptor superfamily cosignaling receptors have been identified that are expressed on T cells, providing fertile ground for development of inhibitory or agonistic antibodies and small molecules as cancer therapeutics. In the current work, we focus on some of the most promising new checkpoints and agonistic or cosignaling molecules that are in early clinical development as single agents or in combinations with PD-1/PD-L1, cytotoxic T-lymphocyte-associated protein 4 blockade, or chemotherapy with an emphasis on those that have reached the clinic and on important targets that are in late preclinical development.

Metastatic insulinoma: current molecular and cytotoxic therapeutic approaches for metastatic well-differentiated panNETs.

Pancreatic neuroendocrine tumors (panNETs) are a type of neuroendocrine tumor with 5-year overall survival rates of approximately 50% when metastasis is present at diagnosis. Tumor grade, as defined by Ki-67 proliferation index, influences overall survival, with low-grade tumors portending a better outcome than intermediate- and high-grade tumors. This case report follows the clinical course and management of a patient with an insulin-secreting metastatic panNET who died 10 years after diagnosis after a treatment course with regional therapy and multiple forms of cytotoxic and molecularly targeted agents. This report presents the various treatment options available for patients with insulin-secreting metastatic panNETs.

Proteomics and ovarian cancer: integrating proteomics information into clinical care.

The power of proteomics allows unparalleled opportunity to query the molecular mechanisms of a malignant cell and the tumor microenvironment in patients with ovarian cancer and other solid tumors. This information has given us insight into the perturbations of signaling pathways within tumor cells and has aided the discovery of new drug targets for the tumor and possible prognostic indicators of outcome and disease response to therapy. Proteomics analysis of serum and ascites has also given us sources with which to discover possible early markers for the presence of new disease and for the progression of established cancer throughout the course of treatment. Unfortunately, this wealth of information has yielded little to date in changing the clinical care of these patients from a diagnostic, prognostic, or treatment perspective. The rational examination and translation of proteomics data in the context of past clinical trials and the design of future clinical trials must occur before we can march forward into the future of personalized medicine.

Apo and ligand-bound structures of ModA from the archaeon Methanosarcina acetivorans.

The trace-element oxyanion molybdate, which is required for the growth of many bacterial and archaeal species, is transported into the cell by an ATP-binding cassette (ABC) transporter superfamily uptake system called ModABC. ModABC consists of the ModA periplasmic solute-binding protein, the integral membrane-transport protein ModB and the ATP-binding and hydrolysis cassette protein ModC. In this study, X-ray crystal structures of ModA from the archaeon Methanosarcina acetivorans (MaModA) have been determined in the apoprotein conformation at 1.95 and 1.69 A resolution and in the molybdate-bound conformation at 2.25 and 2.45 A resolution. The overall domain structure of MaModA is similar to other ModA proteins in that it has a bilobal structure in which two mixed alpha/beta domains are linked by a hinge region. The apo MaModA is the first unliganded archaeal ModA structure to be determined: it exhibits a deep cleft between the two domains and confirms that upon binding ligand one domain is rotated towards the other by a hinge-bending motion, which is consistent with the 'Venus flytrap' model seen for bacterial-type periplasmic binding proteins. In contrast to the bacterial ModA structures, which have tetrahedral coordination of their metal substrates, molybdate-bound MaModA employs octahedral coordination of its substrate like other archaeal ModA proteins.