Cancer immunotherapy targeting neoantigens

AbstractNeoantigens are antigens encoded by tumor-specific mutated genes. Studies in the past few years have suggested a key role for neoantigens in cancer immunotherapy. Here we review the discoveries of neoantigens in the past two decades and the current advances in neoantigen identification. We also discuss the potential benefits and obstacles to the development of effective cancer immunotherapies targeting neoantigens

Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapy.

Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TILs) targeting neoantigens can mediate tumor regression in selected patients with metastatic epithelial cancer. However, effectively identifying and harnessing neoantigen-reactive T cells for patient treatment remains a challenge and it is unknown whether current methods to detect neoantigen-reactive T cells are missing potentially clinically relevant neoantigen reactivities. We thus investigated whether the detection of neoantigen-reactive TILs could be enhanced by enriching T cells that express PD-1 and/or T cell activation markers followed by microwell culturing to avoid overgrowth of nonreactive T cells. In 6 patients with metastatic epithelial cancer, this method led to the detection of CD4+ and CD8+ T cells targeting 18 and 1 neoantigens, respectively, compared with 6 and 2 neoantigens recognized by CD4+ and CD8+ T cells, respectively, when using our standard TIL fragment screening approach. In 2 patients, no recognition of mutated peptides was observed using our conventional screen, while our high-throughput approach led to the identification of 5 neoantigen-reactive T cell receptors (TCRs) against 5 different mutations from one patient and a highly potent MHC class II-restricted KRASG12V-reactive TCR from a second patient. In addition, in a metastatic tumor sample from a patient with serous ovarian cancer, we isolated 3 MHC class II-restricted TCRs targeting the TP53G245S hot-spot mutation. In conclusion, this approach provides a highly sensitive platform to isolate clinically relevant neoantigen-reactive T cells or their TCRs for cancer treatment

Impact of Irminger Rings on Deep Convection in the Labrador Sea : mooring instrument, cruise CTD, and APEX data report September 2007 – September 2009

This is the final data report of all hydrographic station, mooring, and subsurface float data collected by the Woods Hole Oceanographic Institution in 2007-2009 during the Impact of Irminger Rings on Deep Convection in the Labrador Sea experiment (IRINGS). The objectives of IRINGS were to (1) to determine the full water column hydrographic and velocity structure of newlyformed Irminger Rings that have entered the interior Labrador Sea; (2) to observe how Irminger Ring core properties are modified by atmospheric forcing over their lifetime; and (3) to improve the interpretation of sea surface height (SSH) anomalies in terms of newly formed coherent heat containing Irminger Rings. The mooring deployment and recovery cruises were both on the R/V Knorr: KN192-01 in September 2007 and KN196-01 in September 2009, respectively. The single mooring held eight Aanderaa current meters (RCM-11), two Submerged Autonomous Launch Platforms (SALPs), and nine Seabird microcats (SBE37), deployed from 26 September 2007 through 27 September 2009, yeilding full water column (100-3000 meters) records of temperature, salinity, pressure, and velocity data for the two year period. The two SALP cages contained eleven APEX floats, and released some of these floats according to local oceanographic conditions, so as to seed the floats in passing Irminger Rings, and the remainder of floats as timed releases. Thirteen conductivity-temperature-depth (CTD) stations were taken on the mooring recovery cruise, creating a boundary current cross-section from the mooring site to Nuuk, Greenland.Funding was provided by the National Science Foundation Grant OCE-0623192

Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model

Exosomes are endosome-derived small membrane vesicles that are secreted by most cell types including tumor cells. Tumor-derived exosomes usually contain tumor antigens and have been used as a source of tumor antigens to stimulate anti-tumor immune responses. However, many reports also suggest that tumor-derived exosomes can facilitate tumor immune evasion through different mechanisms, most of which are antigen-independent. In the present study we used a mouse model of delayed-type hypersensitivity (DTH) and demonstrated that local administration of tumor-derived exosomes carrying the model antigen chicken ovalbumin (OVA) resulted in the suppression of DTH response in an antigen-specific manner. Analysis of exosome trafficking demonstrated that following local injection, tumor-derived exosomes were internalized by CD11c+ cells and transported to the draining LN. Exosome-mediated DTH suppression is associated with increased mRNA levels of TGF-β1 and IL-4 in the draining LN. The tumor-derived exosomes examined were also found to inhibit DC maturation. Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs. © 2011 Yang et al

Hall Normalization Constants for the Bures Volumes of the n-State Quantum Systems

We report the results of certain integrations of quantum-theoretic interest, relying, in this regard, upon recently developed parameterizations of Boya et al of the n x n density matrices, in terms of squared components of the unit (n-1)-sphere and the n x n unitary matrices. Firstly, we express the normalized volume elements of the Bures (minimal monotone) metric for n = 2 and 3, obtaining thereby "Bures prior probability distributions" over the two- and three-state systems. Then, as an essential first step in extending these results to n > 3, we determine that the "Hall normalization constant" (C_{n}) for the marginal Bures prior probability distribution over the (n-1)-dimensional simplex of the n eigenvalues of the n x n density matrices is, for n = 4, equal to 71680/pi^2. Since we also find that C_{3} = 35/pi, it follows that C_{4} is simply equal to 2^{11} C_{3}/pi. (C_{2} itself is known to equal 2/pi.) The constant C_{5} is also found. It too is associated with a remarkably simple decompositon, involving the product of the eight consecutive prime numbers from 2 to 23. We also preliminarily investigate several cases, n > 5, with the use of quasi-Monte Carlo integration. We hope that the various analyses reported will prove useful in deriving a general formula (which evidence suggests will involve the Bernoulli numbers) for the Hall normalization constant for arbitrary n. This would have diverse applications, including quantum inference and universal quantum coding.Comment: 14 pages, LaTeX, 6 postscript figures. Revised version to appear in J. Phys. A. We make a few slight changes from the previous version, but also add a subsection (III G) in which several variations of the basic problem are newly studied. Rather strong evidence is adduced that the Hall constants are related to partial sums of denominators of the even-indexed Bernoulli numbers, although a general formula is still lackin