Immunotherapies targeting immune checkpoints have proven efficacious in reducing the burden of
lung cancer in patients; however, the antigenic targets of these reinvigorated T cells remain poorly defined.
Lung cancer tumors contain tumor-associated macrophages (TAM) and neutrophils, which release the
serine proteases neutrophil elastase (NE) and
proteinase 3 (P3) into the tumor microenvironment. NE and P3 shape the antitumor adaptive immune response in
breast cancer and
melanoma. In this report, we demonstrate that
lung cancer cells cross-presented the
tumor-associated
antigen PR1, derived from NE and P3. Additionally, NE and P3 enhanced the expression of
human leukocyte antigen (HLA) class I molecules on
lung cancer cells and induced unique, endogenous
peptides in the immunopeptidome, as detected with mass spectrometry sequencing.
Lung cancer patient tissues with high intratumoral TAMs were enriched for MHC class I genes and T-cell markers, and patients with high TAM and cytotoxic T lymphocyte (CTL) infiltration had improved overall survival. We confirmed the immunogenicity of unique, endogenous
peptides with cytotoxicity assays against
lung cancer cell lines, using CTLs from healthy donors that had been expanded against select
peptides. Finally, CTLs specific for
serine proteases-induced endogenous
peptides were detected in
lung cancer patients using
peptide/HLA-A2 tetramers and were elevated in tumor-infiltrating lymphocytes. Thus,
serine proteases in the tumor microenvironment of
lung cancers promote the presentation of HLA class I immunogenic
peptides that are expressed by
lung cancer cells, thereby increasing the
antigen repertoire that can be targeted in
lung cancer.
Cancer Immunol Res; 5(4); 319-29. ©2017 AACR.