Structural characterization and AlphaFold modeling of human T cell receptor recognition of NRAS cancer neoantigens.

T cell receptors (TCRs) that recognize cancer neoantigens are important for anti-cancer immune responses and immunotherapy. Understanding the structural basis of TCR recognition of neoantigens provides insights into their exquisite specificity and can enable design of optimized TCRs. We determined crystal structures of a human TCR in complex with NRAS Q61K and Q61R neoantigen peptides and HLA-A1 MHC, revealing the molecular underpinnings for dual recognition and specificity versus wild-type NRAS peptide. We then used multiple versions of AlphaFold to model the corresponding complex structures, given the challenge of immune recognition for such methods. Interestingly, one implementation of AlphaFold2 (TCRmodel2) was able to generate accurate models of the complexes, while AlphaFold3 also showed strong performance, although success was lower for other complexes. This study provides insights into TCR recognition of a shared cancer neoantigen, as well as the utility and practical considerations for using AlphaFold to model TCR-peptide-MHC complexes.

Advances, opportunities and challenges in developing therapeutic cancer vaccines.

Therapeutic cancer vaccines have shown promising efficacy in helping immunotherapy for cancer patients, but the systematic characterization of the clinical application and the method for improving efficacy is lacking. Here, we mainly summarize the classification of therapeutic cancer vaccines, including protein vaccines, nucleic acid vaccines, cellular vaccines and anti-idiotypic antibody vaccines, and subdivide the above vaccines according to different types and delivery forms. Additionally, we outline the clinical efficacy and safety of vaccines, as well as the combination strategies of therapeutic cancer vaccines with other therapies. This review will provide a detailed overview and rationale for the future clinical application and development of therapeutic cancer vaccines.

Structural basis for T cell recognition of cancer neoantigens and implications for predicting neoepitope immunogenicity.

Adoptive cell therapy (ACT) with tumor-specific T cells has been shown to mediate durable cancer regression. Tumor-specific T cells are also the basis of other therapies, notably cancer vaccines. The main target of tumor-specific T cells are neoantigens resulting from mutations in self-antigens over the course of malignant transformation. The detection of neoantigens presents a major challenge to T cells because of their high structural similarity to self-antigens, and the need to avoid autoimmunity. How different a neoantigen must be from its wild-type parent for it to induce a T cell response is poorly understood. Here we review recent structural and biophysical studies of T cell receptor (TCR) recognition of shared cancer neoantigens derived from oncogenes, including p53R175H, KRASG12D, KRASG12V, HHATp8F, and PIK3CAH1047L. These studies have revealed that, in some cases, the oncogenic mutation improves antigen presentation by strengthening peptide-MHC binding. In other cases, the mutation is detected by direct interactions with TCR, or by energetically driven or other indirect strategies not requiring direct TCR contacts with the mutation. We also review antibodies designed to recognize peptide-MHC on cell surfaces (TCR-mimic antibodies) as an alternative to TCRs for targeting cancer neoantigens. Finally, we review recent computational advances in this area, including efforts to predict neoepitope immunogenicity and how these efforts may be advanced by structural information on peptide-MHC binding and peptide-MHC recognition by TCRs.

How does TCR-T cell therapy exhibit a superior anti-tumor efficacy.

TCR-engineered T cells have achieved great progress in solid tumor therapy, some of which have been applicated in clinical trials. Deep knowledge about the current progress of TCR-T in tumor therapy would be beneficial to understand the direction. Here, we classify tumor antigens into tumor-associated antigens, tumor-specific antigens, tumor antigens expressed by oncogenic viruses, and tumor antigens caused by abnormal protein modification; Then we detail the TCR-T cell therapy effects targeting those tumor antigens in clinical or preclinical trials, and propose that neoantigen specific TCR-T cell therapy is expected to be a promising approach for solid tumors; Furthermore, we summarize the optimization strategies, such as tumor microenvironment, TCR pairing and affinity, to improve the therapeutic effect of TCR-T. Overall, this review provides inspiration for the antigen selection and therapy strategies of TCR-T in the future.

T cell receptors employ diverse strategies to target a p53 cancer neoantigen.

Adoptive cell therapy with tumor-specific T cells can mediate durable cancer regression. The prime target of tumor-specific T cells are neoantigens arising from mutations in self-proteins during malignant transformation. To understand T cell recognition of cancer neoantigens at the atomic level, we studied oligoclonal T cell receptors (TCRs) that recognize a neoepitope arising from a driver mutation in the p53 oncogene (p53R175H) presented by the major histocompatibility complex class I molecule HLA-A2. We previously reported the structures of three p53R175H-specific TCRs (38-10, 12-6, and 1a2) bound to p53R175H and HLA-A2. The structures showed that these TCRs discriminate between WT and mutant p53 by forming extensive interactions with the R175H mutation. Here, we report the structure of a fourth p53R175H-specific TCR (6-11) in complex with p53R175H and HLA-A2. In contrast to 38-10, 12-6, and 1a2, TCR 6-11 makes no direct contacts with the R175H mutation, yet is still able to distinguish mutant from WT p53. Structure-based in silico mutagenesis revealed that the 60-fold loss in 6-11 binding affinity for WT p53 compared to p53R175H is mainly due to the higher energetic cost of desolvating R175 in the WT p53 peptide during complex formation than H175 in the mutant. This indirect strategy for preferential neoantigen recognition by 6-11 is fundamentally different from the direct strategies employed by other TCRs and highlights the multiplicity of solutions to recognizing p53R175H with sufficient selectivity to mediate T cell killing of tumor but not normal cells.

Structural assessment of HLA-A2-restricted SARS-CoV-2 spike epitopes recognized by public and private T-cell receptors.

T cells play a vital role in combatting SARS-CoV-2 and forming long-term memory responses. Whereas extensive structural information is available on neutralizing antibodies against SARS-CoV-2, such information on SARS-CoV-2-specific T-cell receptors (TCRs) bound to their peptide-MHC targets is lacking. Here we determine the structures of a public and a private TCR from COVID-19 convalescent patients in complex with HLA-A2 and two SARS-CoV-2 spike protein epitopes (YLQ and RLQ). The structures reveal the basis for selection of particular TRAV and TRBV germline genes by the public but not the private TCR, and for the ability of the TCRs to recognize natural variants of RLQ but not YLQ. Neither TCR recognizes homologous epitopes from human seasonal coronaviruses. By elucidating the mechanism for TCR recognition of an immunodominant yet variable epitope (YLQ) and a conserved but less commonly targeted epitope (RLQ), this study can inform prospective efforts to design vaccines to elicit pan-coronavirus immunity.

Systemic Analysis of the DNA Replication Regulator MCM Complex in Ovarian Cancer and Its Prognostic Value.

Microliposome maintenance (MCM) 2, MCM3, MCM4, MCM5, MCM6, and MCM7 are DNA replication regulators and are involved in the progression of multiple cancer types, but their role in ovarian cancer is still unclear. The purpose of this study is to clarify the biological function and prognostic value of the MCM complex in ovarian cancer (OS) progression. We analyzed DNA alterations, mRNA and protein levels, protein structure, PPI network, functional enrichment, and prognostic value in OC based on the Oncomine, cBioPortal, TCGA, CPTAC, PDB, GeneMANIA, DAVID, KEGG, and GSCALite databases. The results indicated that the protein levels of these DNA replication regulators were increased significantly. Moreover, survival analysis showed a prognostic signature based on the MCM complex, which performed moderately well in terms of OS prognostic prediction. Additionally, protein structure, functional enrichment, and PPI network analyses indicated that the MCM complex synergistically promoted OC progression by accelerating DNA replication and the cell cycle. In conclusion, our study suggested that the MCM complex might be a potential target and prognostic marker for OC patients.

FGFR-TKI resistance in cancer: current status and perspectives.

Fibroblast growth factor receptors (FGFRs) play key roles in promoting the proliferation, differentiation, and migration of cancer cell. Inactivation of FGFRs by tyrosine kinase inhibitors (TKI) has achieved great success in tumor-targeted therapy. However, resistance to FGFR-TKI has become a concern. Here, we review the mechanisms of FGFR-TKI resistance in cancer, including gatekeeper mutations, alternative signaling pathway activation, lysosome-mediated TKI sequestration, and gene fusion. In addition, we summarize strategies to overcome resistance, including developing covalent inhibitors, developing dual-target inhibitors, adopting combination therapy, and targeting lysosomes, which will facilitate the transition to precision medicine and individualized treatment.

BDNF and nicotine dependence: associations and potential mechanisms.

Smoking is the leading preventable cause of death worldwide and tobacco addiction has become a serious public health problem. Nicotine is the main addictive component of tobacco, and the majority of people that smoke regularly develop nicotine dependence. Nicotine addiction is deemed to be a chronic mental disorder. Although it is well known that nicotine binds to the nicotinic acetylcholine receptors (nAChRs) and activates the mesolimbic dopaminergic system (MDS) to generate the pleasant and rewarding effects, the molecular mechanisms of nicotine addiction are not fully understood. Brain-derived neurotrophic factor (BDNF) is the most prevalent growth factor in the brain, which regulates neuron survival, differentiation, and synaptic plasticity, mainly through binding to the high affinity receptor tyrosine kinase receptor B (TrkB). BDNF gene polymorphisms are associated with nicotine dependence and blood BDNF levels are altered in smokers. In this review, we discussed the effects of nicotine on BDNF expression in the brain and summarized the underlying signaling pathways, which further indicated BDNF as a key regulator in nicotine dependence. Further studies that aim to understand the neurobiological mechanism of BDNF in nicotine addcition would provide a valuable reference for quitting smoking and developing the treatment of other addictive substances.

Structural basis for oligoclonal T cell recognition of a shared p53 cancer neoantigen.

Adoptive cell therapy (ACT) with tumor-specific T cells can mediate cancer regression. The main target of tumor-specific T cells are neoantigens arising from mutations in self-proteins. Although the majority of cancer neoantigens are unique to each patient, and therefore not broadly useful for ACT, some are shared. We studied oligoclonal T-cell receptors (TCRs) that recognize a shared neoepitope arising from a driver mutation in the p53 oncogene (p53R175H) presented by HLA-A2. Here we report structures of wild-type and mutant p53-HLA-A2 ligands, as well as structures of three tumor-specific TCRs bound to p53R175H-HLA-A2. These structures reveal how a driver mutation in p53 rendered a self-peptide visible to T cells. The TCRs employ structurally distinct strategies that are highly focused on the mutation to discriminate between mutant and wild-type p53. The TCR-p53R175H-HLA-A2 complexes provide a framework for designing TCRs to improve potency for ACT without sacrificing specificity.

Hyperandrogenemia and insulin resistance: The chief culprit of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common systemic reproductive endocrine diseases, which has a variety of effects on a woman's health. Because of the involvement of multiple pathways and the lack of common clues, PCOS demonstrates multifactorial properties and heterogeneity of symptoms. Recent studies have demonstrated that the core etiology and primary endocrine characteristics of PCOS are hyperandrogenemia (HA) and insulin resistance (IR). HA and IR are the main causes of PCOS and they can interplay each other in the occurrence and development of PCOS. Just because of this, the study about the effects of HA and IR on pathophysiology of various related symptoms of PCOS is very important to understand the pathogenesis of PCOS. This paper reviews the main symptoms of PCOS, including neuroendocrine disorders, reproductive processes, dyslipidemia, obesity, hypertension, nonalcoholic fatty liver disease (NAFLD), and sleep disordered breathing, which seriously affect the physical and mental health of PCOS women. The increasing knowledge of the development pattern of HA and IR in PCOS suggests that changes in diet and lifestyle, and the discovery of potential therapeutic agents may improve PCOS. However, further studies are needed to clarify the mutual influence and relation of HA and IR in development of PCOS. This review provides an overview of the current knowledge about the effects of HA and IR on PCOS.

Multi-system reproductive metabolic disorder: significance for the pathogenesis and therapy of polycystic ovary syndrome (PCOS).

Polycystic ovary syndrome (PCOS), a multisystem disease, is a major reason for female infertility around the world. It is no longer considered simply as a disease of ovary. Now researchers growing awareness of the multisystem features of this disease. PCOS has a higher relationship with metabolic disturbance and hypothalamic-pituitary-ovarian axis (HPOA) function disorders. This syndrome results in hyperandrogenemia (HA), hyperinsulinemia/insulin resistance (IR), increased estrone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) ratio imbalance, infertility, cardiovascular diseases, endometrial dysfunction, obesity, and including a litany of other health issues. Furthermore, PCOS has been garnered in recent times. Interventions like metformin, orlistat, hormonal contraceptives, GLP1 agonists, and VitD have been applied to ameliorate or reverse the pathological characterization of PCOS. Moreover, drug-combined therapy of PCOS is superior to single drug administration. This review will focus on the recent progress in pathogenesis and therapy of PCOS.

Association of PD-L1 gene rs4143815 C>G polymorphism and human cancer susceptibility: A systematic review and meta-analysis.

Programmed death ligand 1(PD-L1) mediated immune escape play important roles in the development of cancer. The gene polymorphism of PD-L1, in particular rs4143815 C > G, has been associated with the cancer risks, but with conflicting results. Therefore, this meta-analysis was aimed to assess the association between rs4143815 C > G and cancer susceptibility. A systematic literature search was performed to select the studies and the pooled odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the strength of association. Eleven eligible studies containing 3711 cases and 3704 controls were enrolled in the meta-analysis. The results suggested that there is a strong association between rs4143815 C > G and the cancer risks (G vs. C: OR = 1.386, 95% CI: 1.132-1.696, p = 0.002; GG vs. CG + CC: OR = 1.843 95% CI: 1.300-2.613, p = 0.002; GG + CG vs. CC: OR = 1.280, 95% CI: 1.040-1.576, p = 0.020). Subgroup analysis based on cancer type suggested that PD-L1 rs4143815 C > G might increase the susceptibility to gastric cancer (G vs. C: OR = 1.842, 95% CI: 1.403-2.418, p < 0.001) and bladder cancer (G vs. C: OR = 2.015, 95% CI: 1.556-2.608, p < 0.001), and genotype GG carriers of PD-L1 rs4143815 C > G might have higher risks of HCC (GG vs. CG + CC: OR = 2.226 95% CI: 1.562-3.172, p < 0.001). PD-L1 rs4143815 C > G might confer an increased cancer risk, indicating this SNP may contribute to the pathogenesis of cancer and might be used as a potential biomarker to predict the susceptibility to cancer.

Association of luteinizing hormone/choriogonadotropin receptor gene polymorphisms with polycystic ovary syndrome risk: a meta-analysis.

To investigate the association between Luteinizing hormone/choriogonadotropin receptor (LHCGR) gene polymorphisms and polycystic ovary syndrome (PCOS). A systematic literature search and meta-analysis using STATA software for included studies. Fourteen case-control studies containing rs13405728, rs4539842, and rs2293275 of LHCGR gene were included, which was comprised of 11,738 PCOS cases and 35,329 controls. Results of the meta-analysis showed a significant association between PCOS and rs13405728 (for G vs. A: OR = 0.735, 95% CI = 0.699-0.773, p<.001; For GG vs. AG + AA: OR = 0.578, 95% CI = 0.436-0.767, p<.001; For GG + AG vs. AA: OR = 0.817, 95% CI = 0.741-0.901, p<.001) in Asian populations, and rs4539842 (for ins/ins vs. ins/non + non/non: OR = 0.686, 95% CI = 0.483-0.974, p=.035) and rs2293275 (for AA vs. AG + GG: OR = 4.115, 95% CI = 1.033-16.38, p=.045) in Caucasian populations, respectively. LHCGR gene variations are population specifically associated with PCOS, which indicated these SNPs in LHCGR may contribute to the pathogenesis of PCOS and could be used as potential biomarkers to predict the risk of PCOS.

LY2874455 potently inhibits FGFR gatekeeper mutants and overcomes mutation-based resistance.

The chemical compound LY2874455 has the potential to overcome drug resistance driven by FGFR gatekeeper mutations. X-ray crystallographic studies provide the structural explanation for why this compound is effective against the FGFR gatekeeper mutations.

Nogo­B receptor in relevant carcinoma: Current achievements, challenges and aims (Review).

The novel neurite outgrowth inhibitor B (Nogo­B) receptor (NgBR) is specific for Nogo­B, which is highly expressed in various human organs and cells, including the lung, liver, kidney, smooth muscle cells, blood vessel endothelial cells and inflammatory cells. Previous studies have indicated that NgBR directly interacts with Nogo­B and is able to independently influence lipid and cholesterol homeostasis, angiogenesis, N­glycosylation, the epithelial-mesenchymal transition, the chemotaxis of endothelial cells and cellular proliferation and apoptosis. These multiple functions and actions of this receptor provide an understanding of the important roles of NgBR in various conditions, including fatty liver, atherosclerosis, intracranial microaneurysms, retinitis pigmentosa and severe neurological impairment. Furthermore, NgBR has been demonstrated to exert protean, multifunctional and enigmatic effects in cancer. The present review summarizes the latest knowledge on the suppressing and activating effects of NgBR, emphasizing its function in cancer. Further basic and medical research on this receptor may provide novel insight into its clinical implications on the prognosis of relevant human cancer types.

The role of mTOR in ovarian Neoplasms, polycystic ovary syndrome, and ovarian aging.

The mammalian target of rapamycin, mTOR, is a serine-threonine protein kinase downstream of the phosphatidylinositol 3-kinase (PI3K)-AKT axis. The pathway can regulate cell growth, proliferation, and survival by activating ribosomal kinases. Recent studies have implicated the mTOR signaling pathway in ovarian neoplasms, polycystic ovary syndrome (PCOS) and premature ovarian failure (POF). Preclinical investigations have demonstrated that the PI3K/AKT/mTOR pathway is frequently activated in the control of various ovarian functions. mTOR allows cancer cells to escape the normal biochemical system and regulates the balance between apoptosis and survival. Some recent studies have suggested that involvement of the mTOR signaling system is an important pathophysiological basis of PCOS. Overexpression of the mTOR pathway can impair the interaction of cumulus cells, lead to insulin resistance, and affect the growth of follicles directly. The roles of mTOR signaling in follicular development have been extensively studied in recent years; abnormalities in this process lead to a series of pathologies such as POF and infertility. To improve understanding of the role of the mTOR signaling pathway in the pathogenesis and development of ovarian diseases, here we review the roles of mTOR signaling in such diseases and discuss the corresponding therapeutic strategies that target this pathway. Clin. Anat. 31:891-898, 2018. © 2018 Wiley Periodicals, Inc.

Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455.

Aberrant FGFR4 signaling has been documented abundantly in various human cancers. The majority of FGFR inhibitors display significantly reduced potency toward FGFR4 compared to FGFR1-3. However, LY2874455 has similar inhibition potency for FGFR1-4 with IC50 less than 6.4 nM. To date, there is no published crystal structure of LY2874455 in complex with any kinase. To better understand the pan-FGFR selectivity of LY2874455, we have determined the crystal structure of the FGFR4 kinase domain bound to LY2874455 at a resolution of 2.35 Å. LY2874455, a type I inhibitor for FGFR4, binds to the ATP-binding pocket of FGFR4 in a DFG-in active conformation with three hydrogen bonds and a number of van der Waals contacts. After alignment of the kinase domain sequence of 4 FGFRs, and superposition of the ATP binding pocket of 4 FGFRs, our structural analyses reveal that the interactions of LY2874455 to FGFR4 are largely conserved in 4 FGFRs, explaining at least partly, the broad inhibitory activity of LY2874455 toward 4 FGFRs. Consequently, our studies reveal new insights into the pan-FGFR selectivity of LY2874455 and provide a structural basis for developing novel FGFR inhibitors that target FGFR1-4 broadly.