Apavaloaei et al. analyzed tumor cell surface expression of MHC-I-associated peptides (MAPs) derived from tumor antigens (TAs) in melanoma and non-small cell lung cancer. The vast majority of detected MAPs were from unmutated genomic regions. Mutated tumor-specific antigens were limited due to low RNA expression and being outside of MAP hotspots. High numbers of unmutated TAs were identified. Responders to anti-PD-1 treatment exhibited a decrease in aberrantly-expressed tumor-specific antigens (aeTSAs), which were found to be highly immunogenic, cancer-specific, and shared between patients.
ABSTRACT: Melanoma and non-small cell lung cancer (NSCLC) display exceptionally high mutational burdens. Hence, immune targeting in these cancers has primarily focused on tumor antigens (TAs) predicted to derive from nonsynonymous mutations. Using comprehensive proteogenomic analyses, we identified 589 TAs in cutaneous melanoma (n = 505) and NSCLC (n = 90). Of these, only 1% were derived from mutated sequences, which was explained by a low RNA expression of most nonsynonymous mutations and their localization outside genomic regions proficient for major histocompatibility complex (MHC) class I-associated peptide generation. By contrast, 99% of TAs originated from unmutated genomic sequences specific to cancer (aberrantly expressed tumor-specific antigens (aeTSAs), n = 220), overexpressed in cancer (tumor-associated antigens (TAAs), n = 165) or specific to the cell lineage of origin (lineage-specific antigens (LSAs), n = 198). Expression of aeTSAs was epigenetically regulated, and most were encoded by noncanonical genomic sequences. aeTSAs were shared among tumor samples, were immunogenic and could contribute to the response to immune checkpoint blockade observed in previous studies, supporting their immune targeting across cancers.
Author Info: (1) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Cana
Author Info: (1) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (2) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (3) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (4) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (5) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (6) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (7) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (8) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (9) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (10) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (11) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (12) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (13) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (14) Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. (15) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, Quebec, Canada. (16) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (17) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. (18) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. (19) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Laboratory of Hematology, GIGA Institute, University of Liege, Liege, Belgium. Walloon Excellence in Life Sciences and Biotechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium. (20) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, Quebec, Canada. (21) Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. Department of Biochemistry, McGill University, Montreal, Quebec, Canada. (22) Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. (23) Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. (24) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. pierre.thibault@umontreal.ca. Department of Chemistry, University of Montreal, Montreal, Quebec, Canada. pierre.thibault@umontreal.ca. (25) Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada. claude.perreault@umontreal.ca. Department of Medicine, University of Montreal, Montreal, Quebec, Canada. claude.perreault@umontreal.ca.
