Head and neck squamous cell carcinoma (HNSCC) patients with a significant tobacco smoking history have a poor prognosis compared to never smokers. We hypothesize the poor prognosis in tobacco smokers with HNSCC is, at least in part, due to ongoing suppression of immune response and that understanding of deregulated signals in each step may provide insights to improve clinical outcomes of HNSCC patients.
We characterized the tumor immune microenvironment (TIM) of HNSCC in a retrospective cohort of 177 current, former, and never smokers. Tumors were subjected to analysis of CD3, CD8, FOXP3, PD-1, PD-L1, and pan-cytokeratin by multiplex immunofluorescence, whole exome sequencing, and RNA sequencing. The immune markers were measured in the tumor core (TC), tumor margin (TM), and stroma (S).
Our data indicate that current smokers have significantly lower numbers of CD8+ cytotoxic T-cells and PD-L1+ cells compared to never- and former-smokers. While tumor mutation burden and mutant-allele tumor heterogeneity score do not associate with smoking status, gene-set enrichment analyses reveal significant suppression of IFN-α and IFN-γ response pathways in current smokers. Gene expression of canonical IFN-response chemokines of the CXCL9, CXCL10, CXCL11/CXCR3 axis are lower in current smokers than in former smokers suggesting decreased immune cell migration to the tumor site.
These results indicate that active tobacco use in HNSCC has an immunosuppressive effect through inhibition of tumor infiltration of cytotoxic T-cells likely as a result of suppression of IFN response pathways. Our study highlights the importance of understanding the interaction between smoking and TIM in light of emerging immune modulators for cancer management and the importance of smoking cessation during treatment with immunotherapy.
Clinical trial identification
Legal entity responsible for the study
The James and Esther King Biomedical Research Grant.
C.H. Chung: Honoraria (self): bristol myers squibb; Honoraria (self): astrazeneca; Honoraria (self): Lilly; Honoraria (self): CUE Biopharma. J. Conejo-Garcia: Honoraria (self): Compass Therapeutics; Honoraria (self): Anixa Biosciences. R. Slebos: Spouse / Financial dependant: Bristol Myers Squibb; Spouse / Financial dependant: AstraZeneca ; Spouse / Financial dependant: CUE Biopharma; Spouse / Financial dependant: Lilly Oncology. All other authors have declared no conflicts of interest.