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Intratumor heterogeneity of gene expression profiles in early stage non-small cell lung cancer (NSCLC)

ABSTRACT: Gene expression profiling of NSCLC tissues let to the establishment of several prognostic, predictive gene signatures with little overlap. To study factors introducing variability into gene expression microarray studies we compared interpatient (patient-to-patient) and intrapatient (tumor sub-sample) variations in gene expression profiles in stage I and II NSCLC tissues. We identified 128 probe sets which showed variable intratumoral expression Four different sites (A,B,C,D) of individual primary tumors and matched distant normal lung tissue (N) from 20 patients were used to establish gene expression patterns captured by Affymetrix HG-U133 Plus 2.0 arrays (n = 100).

ORGANISM(S): Homo sapiens

SUBMITTER: Meister Michael

PROVIDER: S-ECPF-GEOD-33532 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Our understanding of the molecular mechanisms underlying postsurgical recurrence of non-small cell lung cancer (NSCLC) is rudimentary. Molecular and T cell repertoire intratumor heterogeneity (ITH) have been reported to be associated with postsurgical relapse; however, how ITH at the cellular level impacts survival is largely unknown. Here we report the analysis of 2880 multispectral images representing 14.2% to 27% of tumor areas from 33 patients with stage I NSCLC, including 17 cases (relapsed within 3 years after surgery) and 16 controls (without recurrence ≥5 years after surgery) using multiplex immunofluorescence. Spatial analysis was conducted to quantify the minimum distance between different cell types and immune cell infiltration around malignant cells. Immune ITH was defined as the variance of immune cells from 3 intratumor regions. We found that tumors from patients having relapsed display different immune biology compared with nonrecurrent tumors, with a higher percentage of tumor cells and macrophages expressing PD-L1 (P =.031 and P =.024, respectively), along with an increase in regulatory T cells (Treg) (P =.018), antigen-experienced T cells (P =.025), and effector-memory T cells (P =.041). Spatial analysis revealed that a higher level of infiltration of PD-L1+ macrophages (CD68+PD-L1+) or antigen-experienced cytotoxic T cells (CD3+CD8+PD-1+) in the tumor was associated with poor overall survival (P =.021 and P =.006, respectively). A higher degree of Treg ITH was associated with inferior recurrence-free survival regardless of tumor mutational burden (P =.022), neoantigen burden (P =.021), genomic ITH (P =.012) and T cell repertoire ITH (P =.001). Using multiregion multiplex immunofluorescence, we characterized ITH at the immune cell level along with whole exome and T cell repertoire sequencing from the same tumor regions. This approach highlights the role of immunoregulatory and coinhibitory signals as well as their spatial distribution and ITH that define the hallmarks of tumor relapse of stage I NSCLC.

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Intratumor heterogeneity of gene expression profiles in early stage non-small cell lung cancer (NSCLC)

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