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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. [ABSTRACT FROM AUTHOR]

The resolution of SARS-CoV-2 replication hinges on cell-mediated immunity, wherein CD8+ T cells play a vital role. Nonetheless, the characterization of the specificity and TCR composition of CD8+ T cells targeting non-spike protein of SARS-CoV-2 before and after infection remains incomplete. Here, we analyzed CD8+ T cells recognizing six epitopes from the SARS-CoV-2 nucleocapsid (N) protein and found that SARS-CoV-2 infection slightly increased the frequencies of N-recognizing CD8+ T cells but significantly enhanced activation-induced proliferation compared to that of the uninfected donors. The frequencies of N-specific CD8+ T cells and their proliferative response to stimulation did not decrease over one year. We identified the N222-230 peptide (LLLDRLNQL, referred to as LLL thereafter) as a dominant epitope that elicited the greatest proliferative response from both convalescent and uninfected donors. Single-cell sequencing of T cell receptors (TCR) from LLL-specific CD8+ T cells revealed highly restricted Vα gene usage (TRAV12-2) with limited CDR3α motifs, supported by structural characterization of the TCR–LLL–HLA-A2 complex. Lastly, transcriptome analysis of LLL-specific CD8+ T cells from donors who had expansion (expanders) or no expansion (non-expanders) after in vitro stimulation identified increased chromatin modification and innate immune functions of CD8+ T cells in non-expanders. These results suggests that SARS-CoV-2 infection induces LLL-specific CD8+ T cell responses with a restricted TCR repertoire. Although SARS-CoV2 epitope characterization has been the focus of extensive research, these efforts have largely focused on the spike protein. Here, the authors demonstrate that CD8+ T cell responses can be directed against a dominant nucleocapsid epitope and rely on a highly focused T cell receptor repertoire. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Competing interests. The authors declare no competing interests.

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., (Copyright © 2018 Elsevier GmbH. All rights reserved.)