Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features

Abstract

The evolution of anti-tumor immune surveillance during initiation and progression of preneoplasia into invasive lung adenocarcinoma (ADC) and its underlying molecular changes are largely unknown. To fill this void, we characterized the immune contexture of invasive lung ADC (n=12) and its precursors of consecutive developmental stages including preneoplasia atypical adenomatous hyperplasia (AAH, n=22), adenocarcinoma in situ (AIS, n=16), minimally invasive adenocarcinoma (MIA, n=28) as well as paired normal lung tissues (NL, n=53) by transcriptomic profiling of 770 genes of nCounter PanCancer Immune Profiling Panel (Nanostring), T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrated that anti-tumor immunity evolved as a continuum from AAH to AIS, MIA and invasive lung ADC with a gradually less effective and more intensely regulated immune response evidenced by down-regulation of immune activation pathways, up-regulation of immunosuppressive pathways, higher infiltration of CD4+ T cells, lower infiltration of CD8+ T cells, increased CD4/CD8 ratio, decreased T cell clonality, lower frequencies of top T cell clones in later stages. Further correlation of these immune features with exome sequencing and methylation data demonstrated that the immune response could be impacted by oncogene mutation status, HLA loss, chromosomal copy number aberrations and DNA methylation aberrations suggesting that only cells in preneoplasia with the ideal combination of these molecular features enabling rapid proliferation and evasion from host immune could outgrow into the dominant clones in invasive lung ADCs. Importantly, the immune activation and evasion have started at preneoplastic stage advocating for immunotherapy in patients with lung ADC precursors for prevention of invasive lung cancers.

Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas

“…7c, Supplementary Fig. 12c) implying a more suppressed T cell infiltrate in later-stage diseases, in line with a concomitant study of immune profiling of the same cohort of IPNs 59 . These findings are consistent with the concept of immune-editing, whereby the immunogenicity of cancer cells evolves under the selective pressure from anti-tumor immune response, resulting in the emergence of immune-resistant cancer clones in later stage diseases.…”

Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas

“…7c and Supplementary Fig. 12c), implying a more suppressed T cell infiltrate in later-stage diseases, in line with a concomitant study of immune profiling of the same cohort of IPNs 59 . These findings are consistent with the concept of immune editing, whereby the immunogenicity of cancer cells evolves under the selective pressure from antitumor immune response, resulting in the emergence of immune-resistant cancer clones in later-stage diseases.…”

Evolution of DNA methylome from precancer to invasive lung adenocarcinoma

“…5C and Supplemental Fig. 8C) implying more suppressed T cell repertoire in later-stage diseases, in line with a concomitant immune profiling study on the same cohort of IPNs 82 . These findings are consistent with the concept of immune-editing, whereby the immunogenicity of cancer cells evolves under the selection pressure from anti-tumor immune response, resulting in the emergence of immune-resistant cancer clone variants in later stage diseases 60 .…”