A team from Fudan University, Shanghai have investigated the problem of highly varied responses in gastric cancer patients given chemotherapy prior to surgery. Previous work in this field has focused heavily on the tumor microenvironment (TME), but here they extended the analysis approach using Olink® Target 96 Inflammation to measure serum proteomics that reflect the systemic immune response in these patients. By monitoring serum proteins before, during and after pre-operative chemotherapy in addition to examining the TME in surgically resected tumor tissue via RNAseq and immunohistochemistry (IHC), they were able to gain a broader insight into molecular and cellular events both locally and systemically, and identify a high performance protein signature to predict drug response.
Responders (R) to chemotherapy tended to have more dynamic systemic immune changes than non-responders (NR) as measured by serum proteins. The TME analysis also showed differences between R/NR: RNA seq indicated changes in pathways associated with immunity, DNA replication and cell cycle, while IHC suggested that tumor infiltration by specific macrophage subtypes was higher in NRs. Interestingly, the post-treatment TME seemed to be more related to pre-treatment serum proteomics than to the post-treatment proteomics. Looking at the predictive value of individual serum proteins, pre-treatment CCL20 and PD-L1 both predicted chemotherapy response with significant accuracy (AUCs of 0.791 and 0.737 respectively). Differences in PD-L1 could also be seen in the post-operative tumor stroma by IHC, but as this was observed prior to start of pre-operative treatment with the Olink data, the protein measurement identifies responders at significantly earlier time point.
Further analysis of the serum proteomics could then identify a 4-protein “pretreatment serum response predictive score (PSRscore)” that could predict the response to pre-operative chemotherapy in gastric cancer patients prior to starting treatment with an AUC of 0.907. Further prognostic evaluations showed that post-treatment serum IL-10RB levels were linked to overall survival and progression-free survival. Overall, the data indicate that research on the TME cannot fully reveal how the immune system responds to gastric cancer and antitumor treatment as a whole and that more efforts should be devoted to profiling systemic immunity in patients with gastric cancer.