Immunotherapy is the treatment of using a patient’s immune system to fight disease which has recently emerged as a vital part of treating certain types of cancer. In particular, immune checkpoint blockade (ICB) therapies that based on inhibitors targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand (PDL-1) have significantly improve the survival of some patients with metastatic cancers. However, response rates to ICB therapies remains a challenge as it rarely exceeded 40%. In this project, we collaborated with Memorial Sloan Kettering Cancer Center to investigate how host germline genetics affects the response to ICB. High-resolution HLA class I genotype was performed on 1,535 advanced cancer patients treated with ICB and determined that maximal heterozygosity at HLA-I loci (“A,”“B,” and “C”) improved overall survival after ICB compared with patients who were homozygous for at least one HLA locus. In two independent melanoma cohorts, patients with the HLA-B44 supertype had extended survival, whereas the HLA-B62 supertype (including HLA-B*15:01) or somatic loss of heterozygosity at HLA-I was associated with poor outcome. Molecular dynamics simulations of HLA-B*15:01 revealed different elements that may impair CD8+ Tcell recognition of neoantigens. The results have important implications for predicting response to immune checkpoint blockade and for the design of neoantigen-based therapeutic vaccines.
B. Infection Diseases
（1) Influenza
Influenza virus is one of the most emergent and fatal diseases of human and poultry. The wide spread of avian flu, including the 1918 H1N1, 1968 H3N2, and more recent H5N1, has caused a great public health concern due to the emergence of potential pandemic threats. Though new vaccines are in development against both H3N2 and H5N1, it is unclear if they will be effective against future strains due to the high mutation rates of the influenza virus. Thus, new techniques that allow for both the prediction of future mutations and the development of appropriate vaccines (consisting of antibodies that can target influenza virus) are in great need for better preparation of future pandemics.
Given that the influenza A virus is under rapid mutations, with substitution rates estimated to be 0.0057 substitutions per site per year for HA1 domain , it is critical to predict future mutations and make an efficient influenza vaccine before a potential variant causes an epidemicor even a pandemic.
In this project, more than 4000 A/H3N2 hemagglutinin (HA) sequences from 1968 to 2008 were analyzed to model the evolutionary path of the influenza virus, which allows us to predict its future potential drifts with specific mutations. The mutual information (MI) method was used to design a site transition network (STN) for each amino acid site in the A/H3N2 HA sequence. The STN network indicates that most of the dynamic interactions are positioned around the epitopes and the receptor binding domain regions, with strong preferences in both the mutation sites and amino acid types being mutated to. The network also shows that antigenic changes accumulate over time, with occasional large changes due to multiple co-occurring mutations at antigenic sites. Furthermore, the cluster analysis by subdividing the STN into several subnetworks reveals a more detailed view about the features of the antigenic change: the characteristic inner sites and the connecting inter-subnetwork sites are both responsible for the drifts. A novel five-step prediction algorithm based on the STN shows a reasonable accuracy in reproducing historical HA mutations. The STN approach also agrees well with the phylogenetic tree and antigenic maps based on HA inhibition assays. Our current prediction strategy might shed light in identifying the trends in the HA sequence evolution, and provide guidelines for future vaccine development.
(2) HIV/AIDS Immune control of viral infections is modulated by diverse T cell receptor (TCR) clonotypes engaging peptide-MHC class I complexes on infected cells, but the relationship between TCR structure and antiviral function is unclear.
In this project, we used a combined approach employing both experimental and theoretical techniques to address the relationship between HIV-1 peptide (KK10)-HLA-TCR complex structure and function. We took advantage of unique reagents generated from persons with untreated HIV-1 infection: intrapatient CTL clones with distinct TCR clonotypes, all induced in vivo against the same HLA B*2705-restricted epitope in Gag, but differing in measures of antiviral function. Using molecular dynamics (MD) simulations coupled with functional assays, we not only captured structural and energetic details of particular substitutions, but also showed that specific binding patterns among KK10-HLA (B*2705)-TCR interactions are associated with enhanced antiviral efficacy and cross-reactivity of the clonotypes. This study provides structural and mechanistic insights into T cell-mediated antiviral immunity in a chronic human viral infection.
C. Type-1 diatetes(T1D)
Type 1 diabetes is a chronic autoimmune disease that can develop at any age, in which the pancreas is not producing enough insulin needed for regulating blood glucose levels. Despite years of research, to date, the exact cause of T1D is still unknown and there is no cure for the disease. In this project, we collaborated with Johns Hopkins University (JHU) and confirmed the discovery of a previously unknown lymphocyte, coined a dual expressor (DE) cell since it is a hybrid between the B lymphocytes and T lymphocytes, which exhibits strong evidence to be a major driver of the autoimmune response that causes T1D. Using large-scale computer simulations, our team worked closely with the experimental collaborators to model the binding of the autoantigen peptides from DE cells to T1D-associated specific immune proteins, Human Leukocyte Antigen proteins (HLA-DQ8). The autoantigen from DE cells was found to bind to HLA-DQ8 molecules over ~10,000 times more strongly than insulin. Further, our simulations revealed an unusual binding behavior, with almost perfect binding registry, for the autoantigen to HLA-DQ8, explaining why the autoantigen produces a strong immune response despite having a different protein sequence from insulin. The results of this work may be valuable to the design of potential immunotherapies for T1D. Specifically, potential vaccinations could be designed so that DE cells are marked harmful and destroyed by the immune system. Likewise, novel therapies could be designed so that DE cells do not elicit a helper T-cell response or stimulate the immune system. Although these solutions require additional investigation, as potential effectual and causal treatments for T1D, they could offer substantial improvement in T1D treatment.
Related Publications:
Diego Chowell, Luc GT Morris, Claud M Grigg, Jeffrey K Weber, Robert M Samstein, Vladimir Makarov, Fengshen Kuo, Sviatoslav M Kendall, David Requena, Nadeem Riaz, Benjamin Greenbaum, James Carroll, Edward Garon, David M Hyman, Ahmet Zehir, David Solit, Michael Berger, R. H. Zhou, Naiyer A Rizvi, Timothy A Chan
Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy,
Science, 359, 582-587, 2018
Z. Xia, J. Gu, J. Zhu and R. H. Zhou,
Using a Mutual Information Based Site Transition Network to Map the Genetic Evolution of Influenza A/H3N2 Virus,
Bioinformatics, 25, 2309-2317, 2009
Z. Xia, H. B. Chen, S. G. Kang, T. Huynh, J. W. Fang, P. A. Lamothe, B. D. Walker, and R. H. Zhou,
The complex and specific pMHC interactions with diverse HIV-1 TCR clonotypes reveal a structural basis for alterations in CTL function,
(Nature) Sci. Rep.4, 4087, 2014
Angelique Hölzemer, Christina F. Thobakgale, Camilo A. Jimenez-Cruz, Wilfredo F. Garcia-Beltran, Jonathan M. Carlson, Nienke H. van Teijlingen, Jaclyn K. Mann, Manjeetha Jaggernath, Seung-gu Kang, Christian Körner, Amy W. Chung, Jamie L. Schafer, David T. Evans, Galit Alter, Bruce D. Walker, Philip J. Goulder, Mary Carrington, Pia Hartmann, Thomas Pertel, R. H. Zhou, Thumbi Ndung’u, Marcus Altfeld,
Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa,
PLoS Medicine, 12, e1001900, 2015
Rizwan Ahmed, Zahra Omidian, Adebola Giwa, Benjamin Cornwell, Neha Majety, David R. Bell, Sangyun Lee, Hao Zhang, Aaron Michels, Stephen Desiderio, Scheherazade Sadegh-Nasseri, Hamid Rabb, Simon Gritsch, Mario L. Suva, Patrick Cahan, Ruhong Zhou, Chunfa Jie, Thomas Donner, and Abdel Rahim A. Hamad,
A Public BCR Present in a Unique Dual-ReceptorExpressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen,
Cell, 177, 1583–1599, 2019
