Immune responses to SARS-CoV-2 in vaccinated patients receiving checkpoint blockade immunotherapy for cancer

Vaccination against SARS-CoV-2 has been successful in protecting patients with cancer from severe infections, but how immune responses against COVID-19 vaccination interact with those elicited during cancer immunotherapy has not been fully described. Immune checkpoint blockade (ICB) disrupts inhibitory pathways in immune cells to improve function and induce tumor immunity but can often cause serious immune related adverse events (IRAEs). Because COVID-19 vaccination and ICB both boost immune responses, it is imperative to understand if combining these regimens causes synergistic enhancement of the immune system. Specifically, whether ICB impacts anti-vaccine immunity in previously vaccinated patients is important since a large percentage of newly diagnosed cancer patients eligible for immunotherapy will have already been vaccinated against COVID-19. To address this, we investigated the influence of ICB on SARS-CoV-2-spike protein (SP) antibody titers and T cell responses in cancer patients previously vaccinated against COVID-19. Human blood samples were collected from 29 vaccinated patients and 12 unvaccinated control patients at baseline (prior to ICB) and following two rounds of ICB infusion. Anti-SARS-CoV-2-SP IgG titers and T cell responses were quantified. Compared to responses at baseline, there was no significant difference in these immune responses after immunotherapy in vaccinated individuals (P=0.4583, P=0.4571, respectively). We interpret these results as evidence that ICB immunotherapy does not significantly enhance SARS-CoV-2-specific antibody titers or T cell responses. Although our study lacks corresponding IRAE rates, the results provide humoral and cellular immunological data that support recent reports documenting the clinical safety and efficacy of COVID-19 vaccination in patients receiving ICB. Additional longitudinal prospective studies, such as the VOICE study (ClinicalTrials.gov identifier NCT04715438) and CAPTURE study (ClinicalTrials.gov identifier NCT03226886), are warranted and will provide broader safety and immunological data defining the effect of systemic cancer therapies on COVID-19 immunity

Gamification through leaderboards : an empirical study in engineering education

Universities are looking for solutions to engage more students in STEM domains and enhance their learning performance (LP). In this context, gamification is put forward as a solution to achieve this aim. The present study examined the effect of gamification – building on leaderboards ‐ on LP. Furthermore, mediating variables, such as intrinsic motivation, self‐efficacy, engagement, and background variables, such as sex, previous gaming experience, and undergraduate major, were considered. A pretest‐posttest quasi‐experimental design with an experimental and a control condition was set up (n = 89) in an Introductory Computer Programming course. We observed a significant improvement in the LP of students in the gamified condition. However, no interaction effect was detected, due to mediating and background variables. The high learning gain is a favorable indicator that gamification might be a promising approach to promote STEM programs

Dissociating Markers of Senescence and Protective Ability in Memory T Cells

No unique transcription factor or biomarker has been identified to reliably distinguish effector from memory T cells. Instead a set of surface markers including IL-7Rα and KLRG1 is commonly used to predict the potential of CD8 effector T cells to differentiate into memory cells. Similarly, these surface markers together with the tumor necrosis factor family member CD27 are frequently used to predict a memory T cell's ability to mount a recall response. Expression of these markers changes every time a memory cell is stimulated and repeated stimulation can lead to T cell senescence and loss of memory T cell responsiveness. This is a concern for prime–boost vaccine strategies which repeatedly stimulate T cells with the aim of increasing memory T cell frequency. The molecular cues that cause senescence are still unknown, but cell division history is likely to play a major role. We sought to dissect the roles of inflammation and cell division history in developing T cell senescence and their impact on the expression pattern of commonly used markers of senescence. We developed a system that allows priming of CD8 T cells with minimal inflammation and without acquisition of maximal effector function, such as granzyme expression, but a cell division history similar to priming with systemic inflammation. Memory cells derived from minimal effector T cells are fully functional upon rechallenge, have full access to non-lymphoid tissue and appear to be less senescent by phenotype upon rechallenge. However, we report here that these currently used biomarkers to measure senescence do not predict proliferative potential or protective ability, but merely reflect initial priming conditions

CD103 Deficiency Prevents Graft-versus-Host Disease but Spares Graft-versus-Tumor Effects Mediated by Alloreactive CD8 T Cells

Graft-versus-host disease (GVHD) remains the main barrier to broader application of allogeneic hematopoietic stem cell transplantation (alloSCT) as a curative therapy for host malignancy. GVHD is mediated by allogeneic T cells directed against histocompatibility antigens expressed by host tissues. Based on previous studies, we postulated that the integrin CD103 is required for CD8-mediated GVHD, but not for graft-versus-tumor effects (GVT).We herein provide evidence in support of this hypothesis. To circumvent the potentially confounding influence of donor CD4 T cells, we developed an alloSCT model in which GVHD mortality is mediated by purified CD8 T cells. In this model, host-reactive CD8 T cells receive CD4 T cell help at the time of initial activation but not in the effector phase in which mature CD8 T effectors migrate into host tissues. We show that donor CD8 T cells from wild-type BALB/c mice primed to host alloantigens induce GVHD pathology and eliminate tumors of host origin in the absence of host CD4 T cells. Importantly, CD103 deficiency dramatically attenuated GVHD mortality, but had no detectable impact on the capacity to eliminate a tumor line of host origin. We provide evidence that CD103 is required for accumulation of donor CD8 T cells in the host intestinal epithelium but not in the tumor or host lymphoid compartments. Consistent with these data, CD103 was preferentially expressed by CD8 T cells infiltrating the host intestinal epithelium but not by those infiltrating the tumor, lamina propria, or lymphoid compartments. We further demonstrate that CD103 expression is not required for classic CD8 effector activities including cytokine production and cytotoxicity.These data indicate that CD103 deficiency inhibits GVHD pathology while sparing anti-tumor effects mediated by CD8 T cells, identifying CD103 blockade as an improved strategy for GVHD prophylaxis

Molecules with ALMA at Planet-forming Scales (MAPS). VI. Distribution of the small organics HCN, C2H, and H2CO

Funding: I.C. was supported by NASA through the NASA Hubble Fellowship grant HST-HF2-51405.001-A awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., for NASA, under contract NAS5-26555. C.W. acknowledges financial support from the University of Leeds, STFC, and UKRI (grant Nos. ST/R000549/1, ST/T000287/1, and MR/T040726/1). J.D.I. acknowledges support from the Science and Technology Facilities Council of the United Kingdom (STFC) under ST/T000287/1.Small organic molecules, such as C2H, HCN, and H2CO, are tracers of the C, N, and O budget in protoplanetary disks. We present high-angular-resolution (10-50 au) observations of C2H, HCN, and H2CO lines in five protoplanetary disks from the Molecules with ALMA at Planet-forming Scales (MAPS) ALMA Large Program. We derive column density and excitation temperature profiles for HCN and C2H, and find that the HCN emission arises in a temperate (20-30 K) layer in the disk, while C2H is present in relatively warmer (20-60 K) layers. In the case of HD 163296, we find a decrease in column density for HCN and C2H inside one of the dust gaps near ~83 au, where a planet has been proposed to be located. We derive H2CO column density profiles assuming temperatures between 20 and 50 K, and find slightly higher column densities in the colder disks around T Tauri stars than around Herbig Ae stars. The H2CO column densities rise near the location of the CO snowline and/or millimeter dust edge, suggesting an efficient release of H2CO ices in the outer disk. Finally, we find that the inner 50 au of these disks are rich in organic species, with abundances relative to water that are similar to cometary values. Comets could therefore deliver water and key organics to future planets in these disks, similar to what might have happened here on Earth. This paper is part of the MAPS special issue of the Astrophysical Journal Supplement.Publisher PDFPeer reviewe

Molecules with ALMA at Planet-forming Scales (MAPS). XVIII. Kinematic substructures in the disks of HD 163296 and MWC 480

Funding: K.Z., K.R.S., J.H., J.B., J.B.B., and I.C. acknowledge the support of NASA through Hubble Fellowship grants HST-HF2-51401.001, HST-HF2-51419.001, HST-HF2-51460.001-A, HSTHF2-51427.001-A, HST-HF2-51429.001-A, and HST-HF2-51405.001-A awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., for NASA, under contract NAS5-26555. A.S.B. acknowledges the studentship funded by the Science and Technology Facilities Council of the United Kingdom (STFC). C.W. acknowledges financial support from the University of Leeds, STFC, and UKRI (grant Nos. ST/R000549/1, ST/T000287/1, MR/T040726/1).We explore the dynamical structure of the protoplanetary disks surrounding HD 163296 and MWC 480 as part of the Molecules with ALMA at Planet-forming Scales (MAPS) large program. Using the J = 2-1 transitions of 12CO, 13CO, and C18O imaged at spatial resolutions of ~0"15 and with a channel spacing of 200 m s-1, we find perturbations from Keplerian rotation in the projected velocity fields of both disks (≲5% of the local Keplerian velocity), suggestive of large-scale (tens of astronomical units in size), coherent flows. By accounting for the azimuthal dependence on the projection of the velocity field, the velocity fields were decomposed into azimuthally averaged orthogonal components, vφ, vr, and vz. Using the optically thick 12CO emission as a probe of the gas temperature, local variations of ≍3 K (≍5% relative changes) were observed and found to be associated with the kinematic substructures. The MWC 480 disk hosts a suite of tightly wound spiral arms. The spirals arms, in conjunction with the highly localized perturbations in the gas velocity structure (kinematic planetary signatures), indicate a giant planet, ~1 MJup, at a radius of ≍245 au. In the disk of HD 163296, the kinematic substructures were consistent with previous studies of Pinte et al. and Teague et al. advocating for multiple ~1 MJup planets embedded in the disk. These results demonstrate that molecular line observations that characterize the dynamical structure of disks can be used to search for the signatures of embedded planets. This paper is part of the MAPS special issue of the Astrophysical Journal Supplement.Publisher PDFPeer reviewe

Molecules with ALMA at Planet-forming Scales (MAPS). XIV. Revealing disk substructures in multiwavelength continuum emission

Funding: I.C. was supported by NASA through the NASA Hubble Fellowship grant HST-HF2-51405.001-A awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., for NASA, under contract NAS5-26555. A.S.B acknowledges the studentship funded by the Science and Technology Facilities Council of the United Kingdom (STFC). C.W. acknowledges financial support from the University of Leeds, STFC and UKRI (grant Nos. ST/R000549/1, ST/T000287/1, MR/T040726/1).Constraining dust properties of planet-forming disks via high-angular-resolution observations is fundamental to understanding how solids are trapped in substructures and how dust growth may be favored or accelerated therein. We use ALMA dust continuum observations of the Molecules with ALMA at Planet-forming Scales (MAPS) disks and explore a large parameter space to constrain the radial distribution of solid mass and maximum grain size in each disk, including or excluding dust scattering. In the nonscattering model, the dust surface density and maximum grain size profiles decrease from the inner disks to the outer disks, with local maxima at the bright ring locations, as expected from dust trapping models. The inferred maximum grain sizes from the inner to outer disks decrease from 1 cm to 1 mm. For IM Lup, HD 163296, and MWC 480 in the scattering model, two solutions are compatible with their observed inner disk emission: one solution corresponding to a maximum grain size of a few millimeters (similar to the nonscattering model), and the other corresponding to a size of a few hundred micrometers. Based on the estimated Toomre parameter, only IM Lup-which shows a prominent spiral morphology in millimeter dust-is found to be gravitationally unstable. The estimated maximum Stokes number in all the disks lies between 0.01 and 0.3, and the estimated turbulence parameters in the rings of AS 209 and HD 163296 are close to the threshold where dust growth is limited by turbulent fragmentation. This paper is part of the MAPS special issue of the Astrophysical Journal Supplement.Publisher PDFPeer reviewe

Detection of Intra-Tumor Self Antigen Recognition during Melanoma Tumor Progression in Mice Using Advanced Multimode Confocal/Two Photon Microscope

Determining how tumor immunity is regulated requires understanding the extent to which the anti-tumor immune response “functions” in vivo without therapeutic intervention. To better understand this question, we developed advanced multimodal reflectance confocal/two photon fluorescence intra-vital imaging techniques to use in combination with traditional ex vivo analysis of tumor specific T cells. By transferring small numbers of melanoma-specific CD8+ T cells (Pmel-1), in an attempt to mimic physiologic conditions, we found that B16 tumor growth alone was sufficient to induce naive Pmel-1 T cell proliferation and acquisition of effector phenotype. Tumor -primed Pmel-1 T cells, are capable of killing target cells in the periphery and secrete IFNγ, but are unable to mediate tumor regression. Within the tumor, Pmel-1 T cells have highly confined mobility, displaying long term interactions with tumor cells. In contrast, adoptively transferred non tumor-specific OT-I T cells show neither confined mobility, nor long term interaction with B16 tumor cells, suggesting that intra-tumor recognition of cognate self antigen by Pmel-1 T cells occurs during tumor growth. Together, these data indicate that lack of anti-tumor efficacy is not solely due to ignorance of self antigen in the tumor microenvironment but rather to active immunosuppressive influences preventing a protective immune response

Molecules with ALMA at Planet-forming Scales (MAPS). XI. CN and HCN as tracers of photochemistry in disks

Funding: I.C. was supported by NASA through the NASA Hubble Fellowship grant HST-HF2-51405.001-A awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., for NASA, under contract NAS5-26555. A.S.B. acknowledges the studentship funded by the Science and Technology Facilities Council of the United Kingdom (STFC). J.D.I. acknowledges support from the Science and Technology Facilities Council of the United Kingdom (STFC) under ST/T000287/1. C.W. acknowledges financial support from the University of Leeds, STFC, and UKRI (grant Nos. ST/R000549/1, ST/T000287/1, MR/T040726/1).UV photochemistry in the surface layers of protoplanetary disks dramatically alters their composition relative to previous stages of star formation. The abundance ratio CN/HCN has long been proposed to trace the UV field in various astrophysical objects; however, to date the relationship between CN, HCN, and the UV field in disks remains ambiguous. As part of the ALMA Large Program MAPS (Molecules with ALMA at Planet-forming Scales), we present observations of CN N = 1-0 transitions at 0.″3 resolution toward five disk systems. All disks show bright CN emission within ~50-150 au, along with a diffuse emission shelf extending up to 600 au. In all sources we find that the CN/HCN column density ratio increases with disk radius from about unity to 100, likely tracing increased UV penetration that enhances selective HCN photodissociation in the outer disk. Additionally, multiple millimeter dust gaps and rings coincide with peaks and troughs, respectively, in the CN/HCN ratio, implying that some millimeter substructures are accompanied by changes to the UV penetration in more elevated disk layers. That the CN/HCN ratio is generally high (>1) points to a robust photochemistry shaping disk chemical compositions and also means that CN is the dominant carrier of the prebiotically interesting nitrile group at most disk radii. We also find that the local column densities of CN and HCN are positively correlated despite emitting from vertically stratified disk regions, indicating that different disk layers are chemically linked. This paper is part of the MAPS special issue of the Astrophysical Journal Supplement.Publisher PDFPeer reviewe

Molecules with ALMA at Planet-forming Scales (MAPS). VIII. CO gap in AS 209-gas depletion or chemical processing?

Funding: I.C. was supported by NASA through the NASA Hubble Fellowship grant HST-HF2-51405.001-A awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., for NASA, under contract NAS5-26555. J.D.I. acknowledges support from the Science and Technology Facilities Council of the United Kingdom (STFC) under ST/T000287/1. C.W. acknowledges financial support from the University of Leeds, SFTC, and UKRI (grant Nos. ST/R000549/1, ST/T000287/1, and MR/T040726/1).Emission substructures in gas and dust are common in protoplanetary disks. Such substructures can be linked to planet formation or planets themselves. We explore the observed gas substructures in AS 209 using thermochemical modeling with RAC2D and high-spatial-resolution data from the Molecules with ALMA at Planet-forming Scales (MAPS) program. The observations of C18O J = 2-1 emission exhibit a strong depression at 88 au overlapping with the positions of multiple gaps in millimeter dust continuum emission. We find that the observed CO column density is consistent with either gas surface-density perturbations or chemical processing, while C2H column density traces changes in the C/O ratio rather than the H2 gas surface density. However, the presence of a massive planet (>0.2 MJup) would be required to account for this level of gas depression, which conflicts with constraints set by the dust emission and the pressure profile measured by gas kinematics. Based on our models, we infer that a local decrease of CO abundance is required to explain the observed structure in CO, dominating over a possible gap-carving planet present and its effect on the H2 surface density. This paper is part of the MAPS special issue of the Astrophysical Journal Supplement.Publisher PDFPeer reviewe