Analysis of the immune landscape of small bowel neuroendocrine tumors

in Endocrine-Related Cancer
Correspondence should be addressed to J Strosberg:
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Immune checkpoint inhibitors have shown promising results in different cancers, and correlation between immune infiltration, expression of programmed death-ligand 1 (PD-L1) by tumor cells and response to immunotherapy has been reported. There is limited knowledge regarding the immune microenvironment of small bowel (SB) neuroendocrine tumors (NETs). This work was aimed at characterizing the immune landscape of SB NETs. Expression of PD-L1 and programmed death-1 (PD-1) was evaluated by immunohistochemistry in 102 surgically resected, primary NETs of the duodenum, jejunum and ileum. Extent and characteristics of the tumor-associated immune infiltrate were also assessed and investigated in their prognostic potential. We detected the expression of PD-L1 in ≥1 and ≥50% of tumor cells in 40/102 (39%; 95% CI, 30–49%) and 14/102 (14%; 95% CI, 8–22%) cases respectively. Intratumor host immune response was apparently absent in 35/102 cases (34%; 95% CI, 25–44%), mild to moderate in 46/102 samples (45%, 95% CI, 35–55%), intense in 21/102 tumors (21%, 95% CI, 13–30%). Expression of PD-L1 and extent of immune infiltration were significantly higher in duodenal NETs as compared with jejunal/ileal NETs. A marked peritumoral host response was organized as ectopic lymph node-like structures in 18/102 cases (18%; 95% CI, 11–26%). Neither PD-L1 expression nor the degree of immune infiltration showed any prognostic significance. Overall, the immune landscape of SB NETs is heterogeneous, with adaptive immune resistance mechanisms prevailing in duodenal NETs. Clinical trials of immune checkpoint inhibitors should take into account the immune heterogeneity of SB NETs.

Downloadable materials

  • Table S1 – Clones, dilutions and timing for immunohistochemistry.
  • Table S2. Criteria for PD-L1 positivity interpretation.
  • Figure S1 – Kaplan-Meier estimates of OS and CSS. (A) OS and (B) CSS in the overall population. (C,E) OS and (D,F) CSS by PD-L1 expression.
  • Figure S2 – Kaplan-Meier estimates of OS and CSS. (A) OS and (B) CSS by the extent of immune infiltration. (C) OS and (D) CSS by ELNs. (E) OS and (F) CSS by intratumor infiltration of PD-1+ lymphocytes.


      Society for Endocrinology

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    PD-L1 expression in FFPE samples of small intestine NETs. (A) Small bowel NETs showed different intensities of PD-L1 expression (1+, weak; 2+, moderate; 3+ intense). Scale bar: 20 µm. By using either the ≥1% (B) or ≥50% (C) cut-offs for positivity interpretation, expression of PD-L1 was more common in duodenal NETs as compared with jejunal/ileal NETs.

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    Histopathologic examples of immune infiltration in SB NETs. (A) Absence of intratumor lymphocyte infiltrates. Examples of mild and intense immune infiltration are depicted in (B) and (C) respectively. Scale bar: 20 µm. (D) ELNs (black arrows) at the invasive tumor edge. Magnification: 200×.

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    Heterogeneity of the immune microenvironment of SB NETs. (A) In the overall cohort, one-third of cases showed features suggestive of adaptive immune resistance. (B) and (C) depict the immune landscape of duodenal and jejunal/ileal NETs respectively. A full color version of this figure is available at

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    Cellular composition of ELNs. By IHC, the cellular makeup of ELNs resembles secondary or tertiary lymphoid structures. (A) CD3+ T cells are mainly located in the parafollicular cortex, with a similar distribution for CD4+ (B) and CD8+ cells (C). CD20+ B cells (D) and CD21+ dendritic cells (E) tend to concentrate in the center of the follicle, where the proliferative activity appears more marked (F). CD27+ memory T cells (G) are localized at the boundary with the T cell zone, with some dispersion into the follicle. Only sporadic FOXP3+ regulatory T cells can be found in the context of lymphoid aggregate (H), while PD-1+ lymphocytes (I) appear to be dispersed throughout the ELN. Magnification: 100×.

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    Immune microenvironment and PD-L1 regulation in SB NETs. After tumor initiation (A), SB NETs are infiltrated by inflammatory cells that produce pro-inflammatory cytokines, thus stimulating the expression of PD-L1 on tumor cells (B). As result of the interaction between PD-L1 on the membrane of tumor cells and PD-1 on the surface of T lymphocytes, cross-primed CD8+ T cells become exhausted and lack their cytotoxic capability, leading to tumor immune escape (C). A full color version of this figure is available at


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