Abstract
Characterizing the evolutionary trajectory and immune profiling of brain metastasis (BM) may provide insights in the development of novel therapeutic strategies. Here, we performed whole-exome sequencing and multiplex immunofluorescence (MIF) of 40 samples from 12 lung adenocarcinoma (LUAD) patients with BM and compared to their paired primary tumors. We observed significantly higher intertumor heterogeneity between paired primary tumors and BMs, with only a median of 8.3% of genetic mutations identified as shared. Phylogenetic analysis revealed that BM-competent clones genetically diverged from their primary tumors at relatively early stage, suggesting that the parallel progression model is dominant. In cases with synchronous lymph node metastasis (LNM), phylogenetic analysis suggested that BM is a later event than LNM. MIF analysis found that BMs exhibited significantly lower CD8+ T cell infiltration (P = 0.048), and elevated CD4+Foxp3+ T cell infiltration (P = 0.036) and PD-1 expression (P = 0.047) in comparison to the matched primary tumors, indicating an immunosuppressive microenvironment in BMs. The current study revealed the discrepancy of mutational landscape as well as tumor immune microenvironment between BM and its primary tumor – such findings shall help us better understand the unique biological features of BM and develop innovative strategies accordingly for our patients with LUAD.
Highlights
Distant metastasis represents ominous progression of various solid tumors including lung cancer[1]
We successfully conducted whole-exome sequencing in 40 samples (12 primary tumors, 12 brain metastasis (BM) lesions, 12 peripheral blood cells, and 4 synchronous lymph nodes metastasis (LNM) lesions) from 12 cases with matched primary lesion and BM (Fig. 1), yielding a median depth of 156× (101–287×)
Elucidating the evolutionary pattern and its impact on mutational landscape and immune profiling of BMs may improve the management of this clinical entity
Summary
Distant metastasis represents ominous progression of various solid tumors including lung cancer[1]. Accumulating evidence suggested that distant metastasis is an evolutionary process through which tumor cells spread from the primary lesions[2,3,4]. Previous genomic analysis of solid tumors and matched BMs revealed significant genetic heterogeneity between primary lesions and BMs10, and the degree of genetic heterogeneity of BMs varied significantly among individuals with NSCLC, breast, and colorectal cancer[11,12,13], indicating intertumor heterogeneity of metastatic disease. A recent study identified several genetic drivers that could promote BM15, the distinct mutational and immune features of BM, as well as its phylogenetic relationship with matched primary lesions and lymph nodes metastasis (LNM) remain largely unknown
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