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Elevated immunity to cancer-expressed antigens can be detected in people with no history of cancer and may contribute to cancer prevention. We have previously reported that MHC-restricted phosphopeptides are cancer-expressed antigens and targets of immune recognition. However, the extent to which this immunity reflects prior or ongoing phosphopeptide exposures was not investigated. In this study, we found that preexisting immune memory to cancer-expressed phosphopeptides was evident in most healthy donors, but the breadth among donors was highly variable. Although three phosphopeptides were recognized by most donors, suggesting exposures to common microbial/infectious agents, most of the 205 tested phosphopeptides were not recognized by peripheral blood mononuclear cells (PBMC) from any donor and the remainder were recognized by only 1 to 3 donors. In longitudinal analyses of 2 donors, effector immune response profiles suggested active reexposures to a subset of phosphopeptides. These findings suggest that the immunogens generating most phosphopeptide-specific immune memory are rare infectious agents or incipient cancer cells with distinct phosphoproteome dysregulations, and that repetitive immunogenic exposures occur in individual donors. Phosphopeptide-specific immunity in PBMCs and tumor-infiltrating lymphocytes from ovarian cancer patients was limited, regardless of whether the phosphopeptide was expressed on the tumor. However, 4 of 10 patients responded to 1 to 2 immunodominant phosphopeptides, and 1 showed an elevated effector response to a tumor-expressed phosphopeptide. As the tumors from these patients displayed many phosphopeptides, these data are consistent with lack of prior exposure or impaired ability to respond to some phosphopeptides and suggest that enhancing phosphopeptide-specific T-cell responses could be a useful approach to improve tumor immunotherapy.

Altered protein phosphorylation in cancer cells often leads to surface presentation of phosphopeptide neoantigens. However, their role in cancer immunogenicity remains unclear. Here we describe a mechanism by which an HLA-B*0702-specific acute myeloid leukemia phosphoneoantigen pMLL747-755 (EPR(pS)PSHSM) is recognized by cognate TCR27, which is a candidate for immunotherapy of AML. We show that the replacement of phosphoserine P4 with serine or phosphomimetics does not affect the pMHC conformation or peptide-MHC affinity but abrogates the TCR27-dependent T cell activation and weakens binding between TCR27 and pMHC. We determined the crystal structures for TCR27 and cognate pMHC, mapped the pMHC-TCR interface by TROSY-NMR, generated a ternary pMHC-TCR complex using information-driven protein docking, and identified key polar interactions between phosphate group at P4 and TCR27 that are crucial for ternary complex stability and TCR27 specificity. These data will support development of cancer immunotherapy through target expansion and TCR optimization. *The authors would like to note that Yury Patskovsky and Aswin Natarajan contributed equally.

This paper reports the results of a design study for an exoplanet imaging system. The design team consisted of the students in the "Electromagnetic Sensing for Space-Bourne Imaging" class taught by the principal author in the Spring, 2005 semester. The design challenge was to devise a space system capable of forming 10X10 pixel images of terrestrial-class planets out to 10 parsecs, observing in the 9.0 to 17.0 microns range. It was presumed that this system would operate after the Terrestrial Planet Finder had been deployed and had identified a number of planetary systems for more detailed imaging. The design team evaluated a large number of tradeoffs, starting with the use of a single monolithic telescope, versus a truss-mounted sparse aperture, versus a formation of free-flying telescopes. Having selected the free-flyer option, the team studied a variety of sensing technologies, including amplitude interferometry, intensity correlation imaging (ICI, based on the Brown-Twiss effect and phase retrieval), heterodyne interferometry and direct electric field reconstruction. Intensity correlation imaging was found to have several advantages. It does not require combiner spacecraft, nor nanometer-level control of the relative positions, nor diffraction-limited optics. Orbit design, telescope design, spacecraft structural design, thermal management and communications architecture trades were also addressed. A six spacecraft design involving non-repeating baselines was selected. By varying the overall scale of the baselines it was found possible to unambiguously characterize an entire multi-planet system, to image the parent star and, for the largest base scales, to determine 10X10 pixel images of individual planets.