Studies on small bowel neuroendocrine tumor microenvironment and immunology

Small bowel neuroendocrine tumors (SB-NETs) are rare, but their incidence has increased during past decades. SB-NETS are usually slow growing tumors with relatively good prognosis, but they can spread locally or present with distant metastases. SB-NETs can be asymptomatic for a long time due to their location, and many have metastasized by the time of the definitive diagnosis. Distantly metastasized and surgically inoperable cases call for novel treatment options. Developing targeted anti-tumoral medications requires better understanding of SB-NET tumor biology.

Inflammation and tumor microenvironment characteristics, such as acidity, have prognostic effect in various tumors. Strong T cell-rich adaptive immune response is typically associated with favorable prognosis. Toll-like receptors (TLRs) of innate immunity recognize foreign, evolutionarily conserved parts of various pathogens and initiate an inflammatory response. TLR expression has been shown to have either negative, neutral, or positive prognostic effect depending on the type of tumor and the type of receptor and signal activation. Acidic microenvironment has been associated with tumor invasion, migration, and treatment resistance. The acidity is controlled in part by monocarboxylate transporters (MCTs).

The study population of this thesis consisted of patients who were diagnosed with SB-NET and were surgically treated in Oulu University Hospital 2000–2018 and Central Finland Central Hospital 2000–2017. Microscopic evaluation of immunohistochemically stained tissue samples of primary tumors and lymph node metastases was completed. The aim was to investigate adaptive immunity by assessing the density of T cell infiltrations and the strength of the inflammation using CD3-, CD4-, CD8-, and FOXP3-markers. The second aim was to evaluate innate immunity through the expression of TLRs 1–9. The third aim was to assess the expression of the pH-regulators MCT1 and MCT4. The goal was to determine if the expression of these markers had prognostic significance or correlation with clinicopathological variables to identify potential targets for the development of novel anti-tumoral medications to treat SB-NET patients.

The results of the thesis were reported in three original publications. The results showed that most SB-NETs presented with measurable adaptive immune responses, but inflammation had no prognostic significance. MCTs 1 and 4 were expressed in SB-NETs and strong primary tumor MCT4-expression associated with better survival. TLRs 1–2 and 4–9 were expressed in SB-NETs. Strong TLR7 expression in lymph node metastases associated with worse survival. The results suggest MCT4 and TLR7 as interesting targets for further research considering SB-NET-targeting anti-tumoral medications.