Patients with stage I NSCLC who have a higher proportion of tumor Treg cells relative to TIL had a significantly higher risk of recurrence. These data may be useful, particularly if combined with a panel of tumor markers, to suggest at the time of diagnosis which patients with seemingly early-stage NSCLC will relapse.

This panel of four serum proteins is valuable in suggesting the diagnosis of lung cancer. These data may be useful for treating patients with an indeterminate pulmonary lesion, and potentially in predicting individuals at high risk for lung cancer.

In contrast to its inhibitory effects on many cells, IL-10 activates CD8+ tumor infiltrating lymphocytes (TILs) and enhances their antitumor activity. However, CD8+ TILs do not routinely express IL-10 as autocrine complement C3 inhibits IL-10 production through complement receptors C3aR and C5aR. CD8+ TILs from C3-deficient mice, however, express IL-10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T cell- and IL-10-dependent manner; human TILs expanded with IL-2 plus IL-10 increase the killing of primary tumors in vitro compared to IL-2 treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the PD-1/PD-L1 immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8+ TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL-10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy.

Cyclophilin A (CypA) was recently reported to be overexpressed in non-small-cell lung cancer, and represents a potentially novel therapeutic target. To determine the role of CypA in oncogenesis, stable RNA interference (RNAi)-mediated knockdown of CypA was established in two non-small-cell lung cancer cell lines (ADLC-5M2 and LC-103H), and these cells were grown as xenografts in severe combined immunodeficient mice. Tumor cell proliferation, apoptosis, and angiogenesis were measured by Ki67, terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling, and CD31 immunohistochemistry, respectively. Tumor glucose metabolism was assessed by fluorodeoxyglucose positron emission tomography imaging. Knockdown of CypA correlated in vivo with slower growth, less fluorodeoxyglucose uptake, decreased proliferation, and a greater degree of apoptosis in the tumors. These results establish the relevance of CypA to tumor growth in vivo, specifically to proliferation and apoptosis. Elucidation of the precise role of CypA in these pathways may lead to new targeted therapies for lung cancer. (Cancer Res 2005; 65(19): 8853-60)

Many abnormalities detected in the thorax by routine conventional imaging studies are benign, yet all require further evaluation because of the concern for cancer. To address this deficiency and develop a serum biomarker for lung cancer, we designed a matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) based platform to display the proteins present in the serum of patients with or without lung cancer, and then challenged the scientific community to analyze these data with the aim of determining specific ion signal differences among the resulting spectra. The most statistically significant ion peak identified by the various analysis algorithms that differentiated the serum of patients with lung cancer from the serum of individuals without lung cancer was found at m/z 11,702. We identified the protein responsible for this ion peak as serum amyloid A (SAA; M(r) = 11,682.7) by partial purification followed by in-gel digestion and peptide mapping. By enzyme-linked immunosorbent assay, we showed SAA to be present at 286 ng/mL in the serum of cancer patients vs. 34.1 ng/mL in the serum of individuals without cancer. These data suggest that the combination of MALDI-TOF MS and computer analysis can be a powerful tool in the search for serum biomarkers of lung cancer and other diseases.

SUMMARY Some patients with cancer never develop metastasis, and their host response may provide cues for innovative treatment strategies. We previously reported an association between autoantibodies against complement factor H (CFH) and early stage lung cancer. CFH prevents complement-mediated cytotoxicity (CDC) by inhibiting formation of cell-lytic membrane attack complexes on self-surfaces. In an effort to translate these findings into a biologic therapy for cancer, we isolated and expressed DNA sequences encoding high affinity human CFH antibodies directly from single, sorted B cells obtained from patients with the antibody. The co-crystal structure of a CFH antibody-target complex shows a conformational change in the target relative to the native structure. This recombinant CFH antibody causes complement activation, release of anaphylatoxins, and promotes CDC of tumor cell lines, and inhibits tumor growth in vivo. The isolation of anti-tumor antibodies derived from single human B cells represents an alternative paradigm in antibody drug discovery.

Ascending pathways to the telencephalon from the secondary gustatory nucleus (SGN), preglomerular tertiary gustatory nucleus (pTGN), and medial preglomerular nucleus (PGm) were examined by tract‐tracing experiments in goldfish Carassius auratus. Tracer injections to the SGN suggest the presence of direct ascending pathways to the supracommissural and the dorsal parts of the ventral telencephalic area, and the medial part of the dorsal telencephalic area (Dm), restricted to its ventral region. The SGN experiments also suggest projections to the pTGN and PGm, and several neuronal types in the primary gustatory centers were newly found to give rise to ascending fibers to the SGN. Injections to the pTGN suggest reciprocal connections of the nucleus with the dorsal region of the Dm (dDm). Injections to the PGm resulted in labeled cells in the dorsal part of the SGN, the secondary general visceral nucleus, and the posterior part of the dorsal telencephalic area, suggesting that this preglomerular nucleus receives gustatory, general visceral, and olfactory inputs. Fibers labeled from the PGm terminated in the central part of the dorsal telencephalic area and the dDm; the latter region contained many labeled somata. The terminal zone of PGm fibers in the dDm is located laterally adjacent to that from the pTGN. Injection experiments to the pTGN and PGm also suggest connections of these nuclei with the inferior lobar nuclei and torus lateralis. Based on the results of the present as well as recent studies, an updated map is provided that shows by and large distinct sensory representation within the goldfish dorsal telencephalic area. J. Comp. Neurol. 520:2475–2499, 2012. © 2012 Wiley Periodicals, Inc.

BACKGROUNDEarly lung carcinoma detection strategies involving imaging studies have yet to demonstrate a reduction in mortality. Identification of serum biomarkers that could complement radiologic studies and facilitate earlier diagnosis of lung carcinoma would be of significant benefit to patients. In the current pilot study, the authors evaluated two overexpressed proteins in lung carcinoma, serum amyloid A (SAA) and macrophage migration inhibitory factor (MIF), as potential diagnostic serum biomarkers for this malignancy.METHODSSerum levels of SAA and MIF were measured in 50 patients using enzyme‐linked immunosorbent assays. The sensitivity, specificity, and accuracy of the markers in detecting lung carcinoma were determined.RESULTSSAA levels in patients with lung carcinoma were greater than in the control patients (P = 0.07). Serum SAA levels did not exhibit a correlation with tumor size or clinical stage and were higher in patients with squamous cell carcinoma than in patients with other histologic disease types. MIF was unable to differentiate patients with lung carcinoma from patients with other diseases.CONCLUSIONSSAA possesses potential utility as a serum biomarker for lung carcinoma, probably in conjunction with other serum markers that improve its diagnostic accuracy. Before a larger study is performed, the discovery of additional biomarkers to enhance the specificity of SAA in the diagnosis of lung carcinoma is recommended. Cancer 2004. © 2004 American Cancer Society.