Immune Checkpoint Blockade (ICB) led to better outcomes in non-small cell lung cancer (NSCLC) but only a subset of patients benefits from current treatment regimens. Different molecular subtypes show diverse treatment responses. It was reported that patients with KRAS-mutant tumors respond better to ICB therapy, in contrast, EGFR-mutant tumors show higher resistance to this type of therapy. In order to evaluate distinctions between these subtypes, a thorough characterization of the immune environment was performed in patients with untreated NSCLC.
To characterize the immune environment, flow cytometry and multiplex immunohistochemistry was used. Additionally, TCR sequencing and RNA sequencing was performed. The findings were validated in public datasets. Therapeutic blockage of CCL20 was tested in a murine in-vivo flank tumor model comparing CCL20-neutralizing antibody to its isotype control.
No apparent difference of immune cell composition was found between the molecular subgroups. Tumor mutational burden (TMB) and PDL1 expression on cancer cells was higher in KRAS-mutant NSCLC. Additionally, expression of TIGIT and CCL20 were upregulated in the same subgroup. CCL20 upregulation, but not TIGIT expression could be validated in the TCGA lung adenocarcinoma cohort. Additionally, higher CCL20 expression was associated with lower survival probability. Upregulation of CCL20 in KRAS-mutated NSCLC-derived cell lines in comparison to wild type and EGFR-mutated cell lines hints at a possible role of KRAS-mediated CCL20 expression. Additionally, in-vivo experiments with a CCL20-blocking antibody showed reduced tumour growth in the treatment group.
Higher TMB and PD-L1 expression, both suggested biomarkers for the prognosis of ICB response, could explain better results in KRAS-mutant NSCLC. Targeting of CCL20 may be a new option for therapy in this subgroup. In-vivo experiments, using CCL20 blocking antibodies, show promising therapeutic opportunities, although current scientific literature is conflicting and a thorough investigation is warranted. In EGFR-mutated lung cancer, additional research is needed to assist therapy decisions.
J. Kargl.
Has not received any funding.
All authors have declared no conflicts of interest.