Wells, D. K. | bioRxiv Science

bioRxiv2020

Prediction of SARS-CoV-2 epitopes across 9360 HLA class I alleles

SummarySARS-CoV-2 T cell response assessment and vaccine development may benefit from an approach that considers the global landscape of the human leukocyte antigen (HLA) proteins. We predicted the binding affinity between 9-mer and 15-mer peptides from the SARS-CoV-2 peptidome for 9,360 class I and 8,445 class II HLA alleles, respectively. We identified 368,145 unique combinations of peptide-HLA complexes (pMHCs) with a predicted binding affinity less than 500nM, and observed significant overlap between class I and II predicted pMHCs. Using simulated populations derived from worldwide HLA frequency data, we identified sets of epitopes predicted in at least 90% of the population in 57 countries. We also developed a method to prioritize pMHCs for specific populations. Collectively, this public dataset and accessible user interface (Shiny app: https://rstudio-connect.parkerici.org/content/13/) can be used to explore the SARS-CoV-2 epitope landscape in the context of diverse HLA types across global populations.Competing Interest StatementK.M.C is a shareholder in Geneoscopy LLC. D.K.W. is a founder, equity holder and receives consulting fees from Immunai. A.R. is supported by the National Institute of Health (R35 CA197633), the Ressler Family Fund, the Agilent Thought Leader Award, a Stand Up to Cancer- Bristol-Meyer Squibb Catalyst Research Grant (Grant Number: SU2C-AACR-CT06-17). This research grant is administered by the American Association for Cancer Research, the scientific partner of SU2C. A.R. is a member researcher at the Parker Institute for Cancer Immunotherapy.View Full Text

immunology↗

bioRxiv2019

Clonal replacement of tumor-specific T cells following PD-1 blockade

Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients. However, which tumor-specific T cells are mobilized following checkpoint blockade remains unclear. Here, we performed paired single-cell RNA- and T cell receptor (TCR)-sequencing on 79,046 cells from site-matched tumors from patients with basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) pre- and post-anti-PD-1 therapy. Tracking TCR clones and transcriptional phenotypes revealed a coupling of tumor-recognition, clonal expansion, and T cell dysfunction: the T cell response to treatment was accompanied by clonal expansions of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, this expansion did not derive from pre-existing tumor infiltrating T cell clones; rather, it comprised novel clonotypes, which were not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells, compared to other distinct T cell phenotypes, and was evident in BCC and SCC patients. These results, enabled by single-cell multi-omic profiling of clinical samples, demonstrate that pre-existing tumor-specific T cells may be limited in their capacity for re-invigoration, and that the T cell response to checkpoint blockade relies on the expansion of a distinct repertoire of T cell clones that may have just recently entered the tumor.

immunology↗