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Despite the significant clinical advances with the use of immune checkpoint inhibitors (ICIs) in a wide range of cancer patients, response rates to the therapy are variable and do not always result in long-term tumor regression. The development of ICI-resistant disease is one of the pressing issue in clinical oncology, and the identification of new targets and combination therapies is a crucial point to improve response rates and duration. Antigen processing and presentation (APP) pathway is a key element for an efficient response to ICI therapy. Indeed, malignancies that do not express tumor antigens are typically poor infiltrated by T cells and unresponsive to ICIs. Therefore, improving tumor immunogenicity potentially increases the success rate of ICI therapy. In this review, we provide an overview of the key elements of the APP machinery that can be exploited to enhance tumor immunogenicity and increase the efficacy of ICI-based immunotherapy.

In this study, we explored whether Nutlin-3a, a well-known, nontoxic small-molecule compound antagonizing the inhibitory interaction of MDM2 with the tumor suppressor p53, may restore ligands for natural killer (NK) cell-activating receptors (NK-AR) on neuroblastoma cells to enhance the NK cell-mediated killing. Neuroblastoma cell lines were treated with Nutlin-3a, and the expression of ligands for NKG2D and DNAM-1 NK-ARs and the neuroblastoma susceptibility to NK cells were evaluated. Adoptive transfer of human NK cells in a xenograft neuroblastoma-bearing NSG murine model was assessed. Two data sets of neuroblastoma patients were explored to correlate p53 expression with ligand expression. Luciferase assays and chromatin immunoprecipitation analysis of p53 functional binding on PVR promoter were performed. Primary neuroblastoma cells were also treated with Nutlin-3a, and neuroblastoma spheroids obtained from one high-risk patient were assayed for NK-cell cytotoxicity. We provide evidence showing that the Nutlin-3a-dependent rescue of p53 function in neuroblastoma cells resulted in (i) increased surface expression of ligands for NK-ARs, thus rendering neuroblastoma cell lines significantly more susceptible to NK cell-mediated killing; (ii) shrinkage of human neuroblastoma tumor masses that correlated with overall survival upon adoptive transfer of NK cells in neuroblastoma-bearing mice; (iii) and increased expression of ligands in primary neuroblastoma cells and boosting of NK cell-mediated disaggregation of neuroblastoma spheroids. We also found that p53 was a direct transcription factor regulating the expression of PVR ligand recognized by DNAM-1. Our findings demonstrated an immunomodulatory role of Nutlin-3a, which might be prospectively used for a novel NK cell-based immunotherapy for neuroblastoma.

Tumor-infiltrating CD8+ T cells have been shown to play a crucial role in controlling tumor progression. However, the recruitment and activation of these immune cells at the tumor site are strictly dependent on several factors, including the presence of dendritic cells (DCs), the main orchestrators of the antitumor immune responses. Among the various DC subsets, the role of cDC1s has been demonstrated in several preclinical experimental mouse models. In addition, the high density of tumor-infiltrating cDC1s has been associated with improved survival in many cancer patients. The ability of cDC1s to modulate antitumor activity depends on their interaction with other immune populations, such as NK cells. This evidence has led to the development of new strategies aimed at increasing the abundance and activity of cDC1s in tumors, thus providing attractive new avenues to enhance antitumor immunity for both established and novel anticancer immunotherapies. In this review, we provide an overview of the various subsets of DCs, focusing in particular on the role of cDC1s, their ability to interact with other intratumoral immune cells, and their prognostic significance on solid tumors. Finally, we outline key therapeutic strategies that promote the immunogenic functions of DCs in cancer immunotherapy.

Tumor-infiltrating lymphocytes play an essential role in improving clinical outcome of neuroblastoma (NB) patients, but their relationship with other tumor-infiltrating immune cells in the T cell-inflamed tumors remains poorly investigated. Here we show that dendritic cells (DCs) and natural killer (NK) cells are positively correlated with T-cell infiltration in human NB, both at transcriptional and protein levels, and associate with a favorable prognosis. Multiplex imaging displays DC/NK/T cell conjugates in the tumor microenvironment of low-risk NB. Remarkably, this connection is further strengthened by the identification of gene signatures related to DCs and NK cells able to predict survival of NB patients and strongly correlate with the expression of PD-1 and PD-L1. In summary, our findings unveil a key prognostic role of DCs and NK cells and indicate their related gene signatures as promising tools for the identification of clinical biomarkers to better define risk stratification and survival of NB patients.

The atmospheric meridional energy transport in the Northern Hemisphere midlatitudes is mainly accomplished by planetary and synoptic waves. A decomposition into wave components highlights the strong seasonal dependence of the transport, with both the total transport and the contributions from planetary and synoptic waves peaking in winter. In both winter and summer months, poleward transport extremes primarily result from a constructive interference between planetary and synoptic motions. The contribution of the mean meridional circulation is close to climatology. Equatorward transport extremes feature a mean meridional equatorward transport in winter, while the planetary and synoptic modes mostly transport energy poleward. In summer, a systematic destructive interference occurs, with planetary modes mostly transporting energy equatorward and synoptic modes again poleward. This underscores that baroclinic conversion dominates regardless of season in the synoptic wave modes, whereas the planetary waves can be either free or forced, depending on the season. Plain Language Summary The atmospheric heat transport from low to high latitudes is the main mechanism through which the climate reequilibrates the latitudinally uneven absorption of solar radiation. The atmospheric transport is fueled by instabilities driven by the presence of temperature differences between low and high latitudes and acts in such a way to reduce such gradient. This is one of the main stabilizing mechanisms of the climate system. In this work, we investigate how motions of different spatial scales contribute to atmospheric heat transports in the Northern Hemisphere. We discover that the relative importance of synoptic and planetary scale atmospheric motions is different in summer and winter. Our analysis delves into the analysis of events associated with extreme heat transport toward high latitudes, where we see a compensating mechanism between synoptic and planetary atmospheric motions. We furthe

Over the last decade, our understanding of climate sensitivity has improved considerably. The climate system shows variability on many timescales, is subject to non-stationary forcing and it is most likely out of equilibrium with the changes in the radiative forcing. Slow and fast feedbacks complicate the interpretation of geological records as feedback strengths vary over time. In the geological past, the forcing timescales were different than at present, suggesting that the response may have behaved differently. Do these insights constrain the climate sensitivity relevant for the present day? In this paper, we review the progress made in theoretical understanding of climate sensitivity and on the estimation of climate sensitivity from proxy records. Particular focus lies on the background state dependence of feedback processes and on the impact of tipping points on the climate system. We suggest how to further use palaeo data to advance our understanding of the currently ongoing climate change.