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Predicting the outcome of immunotherapy treatment in melanoma patients is challenging. Alterations in genes involved in antigen presentation and the interferon gamma (IFNγ) pathway play an important role in the immune response to tumors. We describe here that the overexpression of PSMB8 and PSMB9 , two major components of the immunoproteasome, is predictive of better survival and improved response to immune-checkpoint inhibitors of melanoma patients. We study the mechanism underlying this connection by analyzing the antigenic peptide repertoire of cells that overexpress these subunits using HLA peptidomics. We find a higher response of patient-matched tumor infiltrating lymphocytes against antigens diferentially presented after immunoproteasome overexpression. Importantly, we find that PSMB8 and PSMB9 expression levels are much stronger predictors of melanoma patientsʼ immune response to checkpoint inhibitors than the tumors’ mutational burden. These results suggest that PSMB8 and PSMB9 expression levels can serve as important biomarkers for stratifying melanoma patients for immune-checkpoint treatment. The response to immunotherapy of melanoma patients is heterogeneous. Here, the authors demonstrate that a high expression of the two major components of the immunoproteasome, PSMB8 and PSMB9, modulates the production of HLA peptides and it is predictive of better survival and improved response to immune-checkpoint inhibitors of melanoma patients.

This study investigated associations among economic status deterioration, mental health, and gender during the COVID-19 pandemic. A total of 1,807 participants completed an online questionnaire that included demographic variables and questions measuring three mental health variables: psychological distress (as measured by symptoms of depression, anxiety, and stress), adjustment disorder, and emotional eating. Results indicated that women reported higher mental health impairment than men. Men and women whose economic status significantly deteriorated because of the COVID-19 pandemic reported greater mental health impairment than those whose economic status did not significantly deteriorate. However, men whose economic status significantly deteriorated reported high mental health impairment (emotional eating and adjustment difficulties) similar to women in the same situation. This change in men’s reporting pattern suggests that the economic impact of COVID-19 severely impacted their mental health and affected how they view their masculinity, which, in turn, further impaired their mental health. As the COVID-19 outbreak has had a significant impact on mental health worldwide, it is important to identify individuals and groups who are at high risk of mental health impairment. The current study demonstrates that men’s distress, which is frequently complex to identify, can be detected using standardized measures and analyzing these according to changes in reporting patterns as opposed to simply examining means and frequencies. The results suggest that the COVID-19 crisis may provide an opportunity to understand more about mental health, in particular, that of men.

Phloem-feeding insects can manipulate plant-induced resistance and are able to suppress effective jasmonic acid/ethylene (JA/ET) defenses by the induction of inefficient salicylic acid (SA) based responses. As a result, activation of the phenylpropanoid biosynthesis pathway in transgenic plants is anticipated to cause complex interactions between phloem-feeding insects and their host plants due to predicted contradiction between two defense forces: the toxicity of various phenylpropanoids and the accumulation of SA via a branch of the activated pathway. Here, we investigated the effect of activating the phenylpropanoids pathway in Nicotiana tabacum, by over-expression of the PAP1 transcription factor, on the whitefly Bemisia tabaci, a phloem-feeding insect model. Our performance assays indicated that the over-expression made the transgenic plants a more suitable host for B. tabaci than wild-type (WT) plants, although these plants accumulated significantly higher levels of flavonoids. Transcription analyses of indicator genes in the SA (PR1a) and JA/ET (ERF1, COI1 and AOC) pathways followed by quantification of the SA and JA hormone levels, indicated that B. tabaci infestation periods longer than 8 hours, caused higher levels of activity of SA signaling in transgenic plants and higher levels of JA/ET signaling in WT plants. Taken together, these results emphasize the important role JA/ET-induced defenses play in protecting plants from successful infestation by B. tabaci and likely other phloem-feeding insects. It also indicates the necessity of phloem feeders to suppress these defenses for efficient utilization of plant hosts. Our data also indicate that the defensive chemistry produced by the phenylpropanoids pathway has only a minor effect on the insect fitness.

A variety of species of bacteria are known to colonize human tumours 1 – 11 , proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment 12 – 14 . However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune response. Here we used 16S rRNA gene sequencing and HLA peptidomics to identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumours. Our analysis of 17 melanoma metastases (derived from 9 patients) revealed 248 and 35 unique HLA-I and HLA-II peptides, respectively, that were derived from 41 species of bacteria. We identified recurrent bacterial peptides in tumours from different patients, as well as in different tumours from the same patient. Our study reveals that peptides derived from intracellular bacteria can be presented by tumour cells and elicit immune reactivity, and thus provides insight into a mechanism by which bacteria influence activation of the immune system and responses to therapy. HLA peptidomic analysis identifies recurrent intracellular bacteria-derived peptides presented on HLA-I and HLA-II molecules in melanoma tumours, revealing how bacteria can modulate immune functions and responses to cancer therapies.

BackgroundThe query for tumor shared and neo-antigens as a therapeutic approach has been the focus of cancer immunology for the past two decades. Notably, these peptide sequences can bind to HLA molecules and present on the cell surface, subsequently to be recognized by T-cell receptors (TCRs), activating the immune system and so facilitating in tumor rejection.1–3 The search for new origins of targetable types of HLA peptides is consistently growing, and new studies show peptides that are derived from non-canonical open reading frames (ORFs), altered translation, proteasome splicing, viral proteins and more.4–6 In light of the new findings, showing the important role of intra-tumor and gut bacteria in tumor-genesis and their effect on the immune response,7–10 we went on a quest for discovering whether intracellular bacteria antigens can be presented by tumor cells, and whether these antigens may elicit an immune response.MethodsCombination of HLA peptidomics with 16S rDNA sequencing.ResultsCombination of HLA peptidomics with 16S rDNA sequencing of 17 melanoma metastasis derived from 9 different patients, lead us to the unbiased identification of an intracellular bacterial peptide repertoire presented on HLA-I and HLA-II molecules. We were able to validate these results by co-culturing the bacterial species identified by 16S sequencing with the patient derived melanoma cells, further validating the peptide’s presentation by preforming HLA peptidomics on the infected cells. Importantly, we were able to identify common bacterial peptides from different metastases of the same patient as well as from different patients. Some of the common bacterial peptides, as well as others, were able to elicit an immune response by the autologous tumor infiltrating lymphocytes (TILs), suggesting potential therapeutic implications of these peptides.ConclusionsThe insights gathered through this study elucidate the effect of intra-tumor bacteria on the immune response and so, may lead to the development of novel clinical applications.ReferencesNeefjes J, Jongsma ML, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol 2011;11: 823–836.Stronen E, Toebes M, Kelderman S, et al. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science 2016; 352: 1337–1341.Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015; 348: 62–68.Chen J, Brunner AD, Cogan JZ, et al. Pervasive functional translation of noncanonical human open reading frames. Science 2020; 367: 1140–1146.Starck SR, Shastri N. Nowhere to hide: unconventional translation yields cryptic peptides for immune surveillance. Immunol Rev 2016;272:8–16.Croft NP, Smith SA, Pickering J, et al. Most viral peptides displayed by class I MHC on infected cells are immunogenic. Proc Natl Acad Sci U S A 2019; 116: 3112–3117.Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359:97–103.Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359:91–97.Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359:104–108.10. Nejman D, Livyatan I, Fuks G et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 2020;368:973–980.

Extensive tumour inflammation, which is reflected by high levels of infiltrating T cells and interferon-γ (IFNγ) signalling, improves the response of patients with melanoma to checkpoint immunotherapy 1 , 2 . Many tumours, however, escape by activating cellular pathways that lead to immunosuppression. One such mechanism is the production of tryptophan metabolites along the kynurenine pathway by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which is induced by IFNγ 3 – 5 . However, clinical trials using inhibition of IDO1 in combination with blockade of the PD1 pathway in patients with melanoma did not improve the efficacy of treatment compared to PD1 pathway blockade alone 6 , 7 , pointing to an incomplete understanding of the role of IDO1 and the consequent degradation of tryptophan in mRNA translation and cancer progression. Here we used ribosome profiling in melanoma cells to investigate the effects of prolonged IFNγ treatment on mRNA translation. Notably, we observed accumulations of ribosomes downstream of tryptophan codons, along with their expected stalling at the tryptophan codon. This suggested that ribosomes bypass tryptophan codons in the absence of tryptophan. A detailed examination of these tryptophan-associated accumulations of ribosomes—which we term ‘W-bumps’—showed that they were characterized by ribosomal frameshifting events. Consistently, reporter assays combined with proteomic and immunopeptidomic analyses demonstrated the induction of ribosomal frameshifting, and the generation and presentation of aberrant trans- frame peptides at the cell surface after treatment with IFNγ. Priming of naive T cells from healthy donors with aberrant peptides induced peptide-specific T cells. Together, our results suggest that IDO1-mediated depletion of tryptophan, which is induced by IFNγ, has a role in the immune recognition of melanoma cells by contributing to diversification of the peptidome landscape. Tryptophan depletion in melanoma cells after prolonged treatment with interferon-γ (IFNγ) results in ribosomal frameshifting and the production of aberrant peptides that can be presented to T cells and induce an immune response.

Generalist insect can utilize two different modes for regulating their detoxification genes, the constitutive mode and the induced mode. Here, we used the Bemisia tabaci sibling species MEAM1 and MED, as a model system for studying constitutive and induced detoxification resistance and their associated tradeoffs. B. tabaci adults were allowed to feed through membranes for 24 h on diet containing only sucrose or sucrose with various phytotoxins. Quantitative real-time PCR analyses of 18 detoxification genes, indicated that relatively few transcripts were changed in both the MEAM1 and MED species, in response to the addition of phytotoxins to the diet. Induced transcription of detoxification genes only in the MED species, in response to the presence of indole-3-carbinol in the insect’s diet, was correlated with maintenance of reproductive performance in comparison to significant reduction in performance of the MEAM1 species. Three genes, COE2 , CYP6-like 5 and BtGST2, responded to more than one compound and were highly transcribed in the insect gut. Furthermore, functional assays showed that the BtGST2 gene encodes a protein capable of interacting with both flavonoids and glucosinolates. In conclusion, several detoxification genes were identified that could potentially be involved in the adaptation of B. tabaci to its host plants.

Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra- and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote \"off-the-shelf\" precision immunotherapies, alleviating limitations of personalized treatments.

Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A·01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra- and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote \"off-the-shelf\" precision immunotherapies, alleviating limitations of personalized treatments.