Zeng et al. developed a mutation-associated neoantigen (MANA) score, based on the expression of ENTPD1, CXCL13, and IL7R, that can identify neoantigen- and tumor-associated antigen-specific TILs across cancers. MANAscore outperformed NeoTCR8 in identifying MANA-specific TILs, and recognized other classes of tumor antigens, including CTAs, ERVs, and viral oncogenes. MANAscore clustered putative tumor-reactive cells with validated tumor-reactive TILs, and displayed distinct anti-PD-1 response T cell trajectories. MANAscore effectively detected tumor-specific T cells within the tumor, but was less effective in the periphery.
Contributed by Shishir Pant
ABSTRACT: Identifying tumor-specific T cell clones that mediate immunotherapy responses remains challenging. Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of CXCL13 and CD39 (ENTPD1), and low IL-7 receptor (IL7R) levels in many cancer types, but their collective relevance to T cell functionality has not been established. Here we present an integrative tool to identify MANA-specific TIL using weighted expression levels of these three genes in lung cancer and melanoma single-cell RNAseq datasets. Our three-gene "MANAscore" algorithm outperforms other RNAseq-based algorithms in identifying validated neoantigen-specific CD8+ clones, and accurately identifies TILs that recognize other classes of tumor antigens, including cancer testis antigens, endogenous retroviruses and viral oncogenes. Most of these TIL are characterized by a tissue resident memory gene expression program. Putative tumor-reactive cells (pTRC) identified via MANAscore in anti-PD-1-treated lung tumors had higher expression of checkpoint and cytotoxicity-related genes relative to putative non-tumor-reactive cells. pTRC in pathologically responding tumors showed distinguished gene expression patterns and trajectories. Collectively, we show that MANAscore is a robust tool that can greatly enrich candidate tumor-specific T cells and be used to understand the functional programming of tumor-reactive TIL.
Author Info: (1) Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, US. Mark Center for Advanced Genomics and Imaging, Baltimore, MD, US. Department of Oncology, Johns Hopkins
Author Info: (1) Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, US. Mark Center for Advanced Genomics and Imaging, Baltimore, MD, US. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, US. (2) Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, US. Mark Center for Advanced Genomics and Imaging, Baltimore, MD, US. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, US. (3) David Geffen School of Medicine, University of California, Los Angeles, CA, US. (4) Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US. (5) Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, US. Mark Center for Advanced Genomics and Imaging, Baltimore, MD, US. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, US. (6) Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US. (7) Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US. Department of Biostatistics, University of Washington, Seattle, WA, US. (8) Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US. (9) Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, US. Mark Center for Advanced Genomics and Imaging, Baltimore, MD, US. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, US. (10) Fred Hutchinson Cancer Center, Seattle, WA, US. Department of Medicine, University of Washington, Seattle, WA, US. (11) Fred Hutchinson Cancer Center, Seattle, WA, US. Department of Medicine, University of Washington, Seattle, WA, US. (12) Fred Hutchinson Cancer Center, Seattle, WA, US. Department of Medicine, University of Washington, Seattle, WA, US. (13) Fred Hutchinson Cancer Center, Seattle, WA, US. Department of Medicine, University of Washington, Seattle, WA, US. (14) Fred Hutchinson Cancer Center, Seattle, WA, US. Department of Medicine, University of Washington, Seattle, WA, US. (15) Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, US. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, US. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, US. (16) Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, US. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, US. (17) Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, US. Mark Center for Advanced Genomics and Imaging, Baltimore, MD, US. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, US. (18) Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US. (19) Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, US. kellie@jhmi.edu. Mark Center for Advanced Genomics and Imaging, Baltimore, MD, US. kellie@jhmi.edu. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, US. kellie@jhmi.edu.
