Global transcriptional profiling of CTLs in tumors and adjacent non-
tumor tissue from treatment-naive patients with early stage
lung cancer revealed molecular features associated with robustness of anti-tumor immune responses. Major differences in the transcriptional program of tumor-infiltrating CTLs were observed that are shared across tumor subtypes.
Pathway analysis revealed enrichment of genes in
cell cycle,
T cell receptor (TCR) activation and co-stimulation pathways, indicating tumor-driven expansion of presumed
tumor antigen-specific CTLs. Marked heterogeneity in the expression of molecules associated with TCR activation and immune checkpoints such as 4-1BB, PD1, TIM3, was also observed and their expression was positively correlated with the density of tumor-infiltrating CTLs. Transcripts linked to tissue-resident memory cells (TRM), such as CD 103, were enriched in tumors containing a
high density of CTLs, and CTLs from CD 103high tumors displayed features of enhanced
cytotoxicity, implying better anti-tumor activity. In an independent cohort of 689
lung cancer patients, patients with CD103high (TRM rich) tumors survived significantly longer. In summary, the
molecular fingerprint of tumor-infiltrating CTLs at the site of
primary tumor was defined and a number of novel targets identified that appear to be important in modulating the magnitude and specificity of anti-tumor immune responses in
lung cancer.