E456: Immune cells in gastrointestinal stromal tumors vary with treatment

Immune cells are a vital component of the tumor microenvironment and are known to play a role in tumor progression and response to therapy. We aim to investigate the changes in immune cell composition in gastrointestinal stromal tumors (GISTs) that are untreated, sensitive, or resistant to the tyrosine kinase inhibitor imatinib.


Methods:

Human GISTs were flash-frozen at the time of surgical resection and processed for bulk RNA sequencing. We combined our 75 samples with 74 from a publicly available database. Bulk gene expression data were analyzed using the immune deconvolution tool CybersortX platform to estimate the proportion of 22 different immune cell types as well as an absolute immune cell expression score. The proportion of immune cells was compared by treatment status and response to imatinib.


Results:

There were 110 untreated, 30 resistant, and 9 sensitive tumors. The most common site was the stomach in the untreated and sensitive groups (62.7% and 66.7%), and the peritoneum in the resistant group (46.7%). The most common mutations were Kit and PDGFRA, with similar distribution in all groups (p=0.64). A high mitotic index ( >5) was seen in 63% of resistant samples and only in the minority of untreated and sensitive (34.5% and 11.1%). The mean absolute immune score was lower in the sensitive group (0.84) compared to untreated (2.54; p< 0.001) and resistant (2.85; p< 0.001) tumors. The most common immune cell types were CD4 cells (38.2%) and tumor-associated macrophages (TAMs, 33%) among all groups. TAM expression was lower in sensitive tumors compared to untreated and resistant tumors (0.29 vs. 0.81 and 1.3; both p< 0.05). Similarly, CD4 cells were significantly decreased in the sensitive samples compared to untreated and resistant tumors (0.24 vs. 1.05 and 0.91; both p< 0.05). There was a significant increase in CD8 cells in the sensitive group compared to untreated (0.05 vs. 0.03; p< 0.05). Regulatory T cells were higher in resistant tumors compared to sensitive and untreated (0.044 vs. 0.016 and 0.037; both p< 0.05).


Conclusions:

Imatinib-sensitive GISTs have a lower immune infiltrate compared to untreated and resistant tumors. They also had a lower absolute expression of TAMs and CD4 and higher CD8 cells, while resistant tumors had more regulatory T cells. These findings highlight the changes in the immune infiltrate in GIST with imatinib treatment. Further understanding the mechanism of these changes could unlock new therapeutic options.