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Abstract Proteins encoded by antigen-processing genes (APGs) provide major histocompatibility complex (MHC) class I (MHC-I) with antigenic peptides. In mammals, polymorphic multigenic MHC-I family is served by monomorphic APGs, whereas in certain nonmammalian species both MHC-I and APGs are polymorphic and coevolve within stable haplotypes. Coevolution was suggested as an ancestral gnathostome feature, presumably enabling only a single highly expressed classical MHC-I gene. In this view coevolution, while optimizing some aspects of adaptive immunity, would also limit its flexibility by preventing the expansion of classical MHC-I into a multigene family. However, some nonmammalian taxa, such as salamanders, have multiple highly expressed MHC-I genes, suggesting either that coevolution is relaxed or that it does not prevent the establishment of multigene MHC-I. To distinguish between these two alternatives, we use salamanders (30 species from 16 genera representing six families) to test, within a comparative framework, a major prediction of the coevolution hypothesis: the positive correlation between MHC-I and APG diversity. We found that MHC-I diversity explained both within-individual and species-wide diversity of two APGs, TAP1 and TAP2, supporting their coevolution with MHC-I, whereas no consistent effect was detected for the other three APGs (PSMB8, PSMB9, and TAPBP). Our results imply that although coevolution occurs in salamanders, it does not preclude the expansion of the MHC-I gene family. Contrary to the previous suggestions, nonmammalian vertebrates thus may be able to accommodate diverse selection pressures with flexibility granted by rapid expansion or contraction of the MHC-I family, while retaining the benefits of coevolution between MHC-I and TAPs.

Changes in classical and nonclassical HLA class I as well as HLA class II antigens have been identified in malignant lesions. These changes, which are described in this review are believed to play a major role in the clinical course of the disease since both HLA class I and class II antigens are critical to the interaction between tumor cells and components of both innate and adaptive immune system. Abnormalities in HLA antigen expression in malignant cells, which range in frequency from 0–90%, are caused by distinct mechanisms. They include defects in β 2 -microglobulin (β 2 m) synthesis, loss of the gene(s) encoding HLA antigen heavy chain(s), mutations, which inhibit HLA antigen heavy chain transcription or translation, defects in the regulatory mechanisms, which control HLA antigen expression and/or abnormalities in one or more of the antigen processing, machinery (APM) components. More recently, epigenetic events associated with tumor development and progression have been found to underlie changes in HLA antigen, APM component, costimulatory molecule and tumor antigen (TA) expression in malignant cells. The types of epigenetic modifications that may occur in normal and malignant cells as well as their role in changes in HLA antigen expression by malignant cells have been reviewed. The epigenetic events associated with alterations in HLA antigen expression may be clinically relevant as, in some cases, they have been shown to impair the recognition of tumor cells by components of the adaptive immune system. The functional relevance and potential clinical significance of these epigenetic alterations have been addressed. Finally, unlike genetic alterations, epigenetic modifications can, in some cases, be reversed with pharmacologic agents that induce DNA hypomethylation or inhibit histone deacetylation. Therefore, strategies to overcome epigenetic modifications underlying changes in HLA antigen expression in malignant cells have been discussed.

BackgroundThe antigen processing machinery (APM) plays a critical role in generating tumor-specific antigens that can be recognized and targeted by the immune system. Proper functioning of APM components is essential for presenting these antigens on the surface of tumor cells, enabling immune detection and destruction. In many cancers, defects in APM can lead to immune evasion, contributing to tumor progression and poor clinical outcomes. However, the status of the APM in sarcomas is not well characterized, limiting the development of effective immunotherapeutic strategies for these patients.MethodsWe investigated 126 patients with 8 types of bone and soft tissue sarcoma operated between 2001–2021. Tissue microarrays mapped 11 specific areas in each case. The presence/absence of APM protein was determined through immunohistochemistry. Bayesian networks were used.ResultsAll investigated sarcomas had some defects in APM. The least damaged component was HLA Class I subunit β2-microglobulin and HLA Class II. The proteasome LMP10 subunit was defective in leiomyosarcoma (LMS), myxoid liposarcoma (MLPS), and dedifferentiated liposarcoma (DDLPS), while MHC I transporting unit TAP2 was altered in undifferentiated pleomorphic sarcoma (UPS), gastrointestinal stromal tumor (GIST), and chordoma (CH). Among different neoplastic areas, high-grade areas showed different patterns of expression compared to high lymphocytic infiltrate areas. Heterogeneity at the patient level was also observed. Loss of any APM component was prognostic of distant metastasis (DM) for LMS and DDLPS and of overall survival (OS) for LMS.ConclusionSarcomas exhibit a high degree of defects in APM components, with differences among histotypes and tumoral areas. The most commonly altered APM components were HLA Class I subunit β2-microglobulin, HLA Class I subunit α (HC10), and MHC I transporting unit TAP2. The loss of APM components was prognostic of DM and OS and clinically relevant for LMS and DDLPS. This study explores sarcoma molecular mechanisms, enriching personalized therapeutic approaches.

Background Transporter associated with antigen processing 1 (TAP1) is a molecule involved in processing and presentation of major histocompatibility complex class I restricted antigens, including tumor-associated antigens. TAP1 participates in tumor immunity, and is aberrantly expressed in multiple cancer types; Methods Transcriptome profiles were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression databases. Genetic alterations, protein distribution, and interaction information for TAP1 were downloaded from cBioPortal, Human Protein Atlas and Compartmentalized Protein–Protein Interaction, respectively. Single-cell analyses of TAP1 across cancers were conducted via the Tumor Immune Single-cell Hub website. Gene set enrichment analysis was employed to investigate TAP1-associated functional mechanisms and processes. Immune cell infiltration was explored using Tumor Immune Estimation Resource 2.0. Pan-cancer correlations between TAP1 expression and immunotherapy biomarkers were explored using the Spearman’s correlation test. Associations with immunotherapy responses were also investigated using clinicopathological and prognostic information from cohorts of patients with cancer receiving immune checkpoint inhibitors. Results TAP1 expression was elevated in most cancer types and exhibited distinct prognostic value. Immune cells expressed more TAP1 than malignant cells within most tumors. TAP1 expression was significantly correlated with immune-related pathways, T-lymphocyte infiltration, and immunotherapeutic biomarkers. Clinical cohort validation revealed a significant correlation with immune therapeutic effects and verified the prognostic role of TAP1 in immunotherapy. Western blot assay indicated that TAP1 is upregulated in glioblastoma compared with adjacent normal brain tissues. Conclusion TAP1 is a robust tumor prognostic biomarker and a novel predictor of clinical prognosis and immunotherapeutic responses in various cancer types.

Until a few years ago, lymphatic vessels and lymphatic endothelial cells (LEC) were viewed as part of a passive conduit for lymph and immune cells to reach lymph nodes (LN). However, recent work has shown that LEC are active immunological players whose interaction with dendritic cells and T cells is of important immunomodulatory relevance. While the immunological interaction between LEC and other immune cells has taken a center stage, molecular analysis of LEC antigen processing and presentation machinery is still lagging. Herein we review the current knowledge of LEC MHC I and MHC II antigen processing and presentation pathways, Including the role of LEC in antigen phagocytosis, classical, and non-classical MHC II presentation, proteasome processing and MHC I presentation, and cross-presentation. The ultimate goal is to provide an overview of the LEC antigen processing and presentation machinery that constitutes the molecular basis for their role in MHC I and MHC II-restricted immune responses.

Somatic mutations in tumor cells give rise to mutant proteins, fragments of which are often presented by MHC and serve as neoantigens. Neoantigens are tumor-specific and not expressed in healthy tissues, making them attractive targets for T-cell-based cancer immunotherapy. On the other hand, since most somatic mutations differ from patient to patient, neoantigen-targeted immunotherapy is personalized medicine and requires their identification in each patient. Computational algorithms and machine learning methods have been developed to prioritize neoantigen candidates. In fact, since the number of clinically relevant neoantigens present in a patient is generally limited, this process is like finding a needle in a haystack. Nevertheless, MHC presentation of neoantigens is not random but follows certain rules, and the efficiency of neoantigen detection may be further improved with technological innovations. In this review, we discuss current approaches to the detection of clinically relevant neoantigens, with a focus on antigen processing and presentation.

ATP-binding cassette (ABC) transporters constitute the largest family of primary active transporters, responsible for many physiological processes and human maladies. However, the mechanism how chemical energy of ATP facilitates translocation of chemically diverse compounds across membranes is poorly understood. Here, we advance the quantitative mechanistic understanding of the heterodimeric ABC transporter TmrAB, a functional homolog of the transporter associated with antigen processing (TAP) by single-turnover analyses at single-liposome resolution. We reveal that a single conformational switch by ATP binding drives unidirectional substrate translocation. After this power stroke, ATP hydrolysis and phosphate release launch the return to the resting state, which facilitates nucleotide exchange and a new round of substrate binding and translocation. In contrast to hitherto existing steady-state assays, our single-turnover approach uncovers the power stroke in substrate translocation and the tight chemomechanical coupling in these molecular machines.

The coronavirus disease 2019 (COVID‐19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has resulted in many deaths throughout the world. It is vital to identify the novel prognostic biomarkers and therapeutic targets to assist with the subsequent diagnosis and treatment plan to mitigate the expansion of COVID‐19. Since angiotensin‐converting enzyme 2 (ACE2)‐positive cells are hosts for COVID‐19, we focussed on this cell type to explore the underlying mechanisms of COVID‐19. In this study, we identified that ACE2‐positive cells from the bronchoalveolar lavage fluid (BALF) of patients with COVID‐19 belong to bronchial epithelial cells. Comparing with patients of COVID‐19 showing severe symptoms, the antigen processing and presentation pathway was increased and 12 typical genes, HLA‐DRB5, HLA‐DRB1, CD74, HLA‐DRA, HLA‐DPA1, HLA‐DQA1, HSP90AA1, HSP90AB1, HLA‐DPB1, HLA‐DQB1, HLA‐DQA2, and HLA‐DMA, particularly HLA‐DPB1, were obviously up‐regulated in ACE2‐positive bronchial epithelial cells of patients with mild disease. We further discovered SDCBP was positively correlated with above 12 genes particularly with HLA‐DPB1 in ACE2‐positive bronchial epithelial cells of COVID‐19 patients. Moreover, SDCBP may increase the immune infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells in different lung carcinoma. Moreover, we found the expression of SDCBP was positively correlated with the expression of antigen processing and presentation genes in post‐mortem lung biopsies tissues, which is consistent with previous discoveries. These results suggest that SDCBP has good potential to be further developed as a novel diagnostic and therapeutic target in the treatment of COVID‐19.

The well described conventional antigen-processing pathway is accountable for most peptides that end up in MHC class I molecules at the cell surface. These peptides experienced liberation by the proteasome and transport by the peptide transporter TAP. However, there are multiple roads that lead to Rome, illustrated by the increasing number of alternative processing pathways that have been reported during last years. Interestingly, TAP-deficient individuals do not succumb to viral infections, suggesting that CD8 T cell immunity is sufficiently supported by alternative TAP-independent processing pathways. To date, a diversity of viral and endogenous TAP-independent peptides have been identified in the grooves of different MHC class I alleles. Some of these peptides are not displayed by normal TAP-positive cells and we therefore called them TEIPP, for \"T-cell epitopes associated with impaired peptide processing.\" TEIPPs are hidden self-antigens, are derived from normal housekeeping proteins, and are processed via unconventional processing pathways. Per definition, TEIPPs are presented via TAP-independent pathways, but recent data suggest that part of this repertoire still depend on proteasome and metalloprotease activity. An exception is the C-terminal peptide of the endoplasmic reticulum (ER)-membrane-spanning ceramide synthase Trh4 that is surprisingly liberated by the signal peptide peptidase (SPP), the proteolytic enzyme involved in cleaving leader sequences. The intramembrane cleaving SPP is thereby an important contributor of TAP-independent peptides. Its family members, like the Alzheimer's related presenilins, might contribute as well, according to our preliminary data. Finally, alternative peptide routing is an emerging field and includes processes like the unfolded protein response, the ER-associated degradation, and autophagy-associated vesicular pathways. These data convince us that there is a world to be discovered in the field of unconventional antigen processing.

Cancer cells frequently display defects in their antigen-processing pathway and thereby evade CD8 T cell immunity. We described a novel category of cancer antigens, named TEIPP, that emerge on cancers with functional loss of the peptide pump TAP. TEIPPs are non-mutated neoantigens despite their ‘self’ origin by virtue of their absence on normal tissues. Here, we describe the development of a synthetic long peptide (SLP) vaccine for the most immunogenic TEIPP antigen identified thus far, derived from the TAP-independent LRPAP1 signal sequence. LRPAP121–30-specific CD8 T cells were present in blood of all tested healthy donors as well as patients with non-small cell lung adenocarcinoma. SLPs with natural flanking, however, failed to be cross-presented by monocyte-derived dendritic cells. Since the C-terminus of LRPAP121–30 is an unconventional and weakly binding serine (S), we investigated if replacement of this anchor would result in efficient cross-presentation. Exchange into a valine (V) resulted in higher HLA-A2 binding affinity and enhanced T cell stimulation. Importantly, CD8 T cells isolated using the V-variant were able to bind tetramers with the natural S-variant and respond to TAP-deficient cancer cells. A functional screen with an array of N-terminal and C-terminal extended SLPs pointed at the 24-mer V-SLP, elongated at the N-terminus, as most optimal vaccine candidate. This SLP was efficiently cross-presented and consistently induced a strong polyclonal LRPAP121–30-specific CD8 T cells from the endogenous T cell repertoire. Thus, we designed a TEIPP SLP vaccine from the LRPAP1 signal sequence ready for validation in clinical trials.