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.

中文翻译：

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从肿瘤形成前到浸润性肺腺癌的免疫进化及其潜在分子特征

肿瘤形成前和进展为浸润性肺腺癌（ADC）期间抗肿瘤免疫监视的演变及其潜在的分子变化在很大程度上尚不清楚。为了填补这一空白，我们表征了侵袭性肺ADC（n = 12）及其连续发展阶段的前体的免疫情况，这些阶段包括neoplasia之前的非典型腺瘤性增生（AAH，n = 22），原位腺癌（AIS，n = 16），微转录腺癌（MIA，n = 28）以及成对的正常肺组织（NL，n = 53）通过对nCounter PanCancer免疫谱分析小组（Nanostring）的770个基因进行转录组分析，T细胞受体（TCR）测序和多重免疫荧光（mIF）。我们的结果表明，抗肿瘤免疫力是从AAH到AIS的连续过程，MIA和侵袭性肺ADC的免疫应答逐渐降低，而免疫调节的强度逐渐增强，其表现为免疫激活途径的下调，免疫抑制途径的上调，CD4 + T细胞的较高浸润，CD8 + T细胞的较低浸润，CD4 / CD8比率，降低的T细胞克隆性，较低频率的晚期T细胞克隆。这些免疫特征与外显子组测序和甲基化数据的进一步相关性表明，免疫应答可能受癌基因突变状态，HLA丢失，染色体拷贝数畸变和DNA甲基化畸变的影响，提示只有在肾上腺髓质变前病变的细胞才具有这些分子特征的理想组合能够使宿主免疫快速增殖和逃逸，可能会超出侵入性肺ADC中的显性克隆。