Immune Gene Expression

RNA from 31 primary and 17 metastatic samples showed that of 730 immune genes, 129 genes (18%) showed lower expression in metastases (P < 0.05). The metastases also showed significantly lower levels of the immune-cell metagenes that are associated with immune-cell activity.

Activated T cells, CD8 cells, T-helper cells, T-regulatory cells, cytotoxic cells, dendritic cells, and mastoid cells were present at a lower level based on mRNA expression. Downregulation was also observed of chemotactic ligands and their corresponding receptors (eg CCL5/CCR5, CCL17/CCR4, IL15/IL15R), which are implicated in the migration of these cells into peripheral tissues.

Transcriptional factors such as NFAT-1 and NFAT-2, which are responsible for the activation of cytotoxic T cells, were also found at low levels in metastatic lesions. According to the researchers, these observations were consistent with an inactive state of T lymphocytes in metastases.

Of the 22 immune functions represented on the Nanostring panel, functions related to T cells, B cells, and NK cells were consistently found at lower levels in the metastatic state, as were functions relating to cytotoxicity, immune regulation, and pathogen defense.

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Of the 29 immune therapeutic targets in clinical development, 13 showed significantly low expression levels, including PD-L1, PD-1, CTLA-4, JAK1, SLAM7, ICOS, and CD27, among others. Prognostic immune gene signatures and signatures predictive for response to pembrolizumab were also lower in metastasis.

“Collectively, these findings indicate not only an immune-depleted, but also an immune-inert, state in metastases,” Dr Pusztai and colleagues noted.

However, components of immune suppression and multiple immune escape mechanisms were preserved in metastatic lesions, and these may suggest potential therapeutic strategies. Targets preserved in metastatic lesions include STAT3, JAK2, TLR1, CSF1, IL8, CCR2, TLR7, TLR8, and LAG3, among others.