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

Abstract

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immuneactivation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in laterstages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC.

Multidimensional profiling depicts infiltrating immune cell heterogeneity in the tumor microenvironment of stage IA non‐small cell lung cancer

“…The immune contexture, particularly the T cell landscape, has been shown to evolve across different stages of early lung cancer pathogenesis. Using immune gene expression profiling data, Dejima et al evaluated the changes in immune cell composition and revealed that the fraction of CD8+ T cells increased from MIA to ADC, 43 consistent with our discovery by mIHC (Figure S3).…”

Tertiary lymphoid structure and decreased CD8+ T cell infiltration in minimally invasive adenocarcinoma

“…Currently, our analysis only revealed associations without having functional validation of the causal effects, although another study reported similar findings in early lung cancers ( Dejima et al., 2020 ). It is challenging to perform the co-culturing of Tfr cells and CD8 + T cells in vitro due to the difficulty of extracting enough Tfr cells.…”

Prognostic role of immune microenvironment in pleural metastases from breast and lung adenocarcinomas

“…Thus, our findings are generally in line with MM tissue studies revealing that CD4 and CD20 are positive prognostic factors, while CD8 and macrophages usually do not reveal prognostic significance. Indeed, a recent analysis of primary lung ADCs and their precursors (28), showed that CD4 + cells increased, while CD8 + cells decreased when moving from normal tissues to ADC precursors and finally invasive lesions. CD8 + T cells are generally considered cytotoxic, however the functions and phenotypes of CD4 + T cells are more heterogenous; there are T helper cells which promote other immune cells and are antitumoral, but also T regulatory cells, which are immune suppressive, favoring tumors (28).…”

“…Indeed, a recent analysis of primary lung ADCs and their precursors (28), showed that CD4 + cells increased, while CD8 + cells decreased when moving from normal tissues to ADC precursors and finally invasive lesions. CD8 + T cells are generally considered cytotoxic, however the functions and phenotypes of CD4 + T cells are more heterogenous; there are T helper cells which promote other immune cells and are antitumoral, but also T regulatory cells, which are immune suppressive, favoring tumors (28). Given that most previous studies in pleural fluid show low levels of T regulatory cells and the fact that the current as well as other studies reveal a positive prognostic role for CD4 + cells, it is very probable that the majority of CD4 + cells detected correspond to T helper cells boosting anti-tumoral activity.…”