Intratumoral genetic and immune microenvironmental heterogeneity in T4N0M0 (diameter ≥ 7 cm) non‐small cell lung cancers

Abstract

Background Starting with low metastatic capability, T4N0M0 (diameter ≥ 7 cm) non‐small cell lung cancers (NSCLCs) constitute a unique tumor subset, as with a large tumor size but no regional or distant metastases. We systematically investigated intratumoral heterogeneity, clonal structure, chromosomal instability (CIN), and immune microenvironment in T4N0M0 (≥7 cm) NSCLCs. Methods Whole‐exome sequencing, RNA sequencing, and multiplex immunohistochemistry (mIHC) staining were conducted to analyze 24 spatially segregated tumor samples from eight patients who were pathologically diagnosed with T4N0M0 (diameter ≥ 7 cm) NSCLCs. The adjacent normal tissues and peripheral blood served as controls. Results In total, 35.2% of mutations and 91.1% of somatic copy number alterations were classified as subclonal events, which exhibited widespread genetic intratumoral heterogeneity. In contrast, a low degree of CIN was observed. None of the patients had genome doubling. The burden of loss of heterozygosity, aneuploidy, and the genome instability index of these tumors were significantly lower than those in the TRACERx cohort. Expression profiles revealed significantly upregulated expression of cell division‐related signals and the G2/M checkpoint pathway. In addition, a similar expression pattern of the immune microenvironment was observed in different regions of the tumor, which was confirmed by mIHC profiles. Conclusions Our study indicates the presence of intratumoral genetic heterogeneity and immune microenvironmental heterogeneity features in T4N0M0 NSCLCs, and the low degree of CIN may be related to the low metastatic capability.

Chromosomal Instability-Driven Cancer Progression: Interplay with the Tumour Microenvironment and Therapeutic Strategies

“…Collectively, these observations indicate that the degree of CIN significantly impacts the composition of immune cell populations within the TME, thereby establishing a nexus between CIN, immune cell infiltration, and their collective impact on the complex landscape of tumourigenesis [89,90]. As such, the cellular composition of the TME has important implications for the immune response to cancer cells, for tumour growth, and for therapeutic strategies.…”

“…The cellular composition of the TME is heavily influenced by a CIN phenotype and resulting aneuploidy in cancer cells as a result of the interaction of cells with CIN and the immune system [84][85][86][87]. However, various contrasting effects of more complex aneuploidy landscapes were reported: some studies have observed increased T cell and macrophage infiltration due to increased immunogenicity from tumour cell genetic diversity, while other studies have shown that tumours with CIN foster an immune-suppressive milieu, preventing the primary CIN-induced immune responses [87][88][89][90]. Likely, these contrasting findings relate to the stage of the tumour, with early CIN + tumours recruiting a tumour-suppressive immune landscape and late tumours circumventing this [91,92].…”

“…Furthermore, ongoing CIN and genome doubling were reported to influence the abundance of infiltrating Treg cells and B cells [88]. Conversely, tumours with low aneuploidy and low metastatic potential displayed increased infiltration by Treg cells and B cells compared to tumours with high aneuploidy rates and high metastatic potential [89,90]. Additionally, transcriptome analyses across multiple cancer types with varying aneuploidy rates showed clear differences between the immune landscapes of tumours with lower versus higher aneuploidy rates [93].…”