Immune Checkpoint Markers in Neuroendocrine Carcinoma of the Digestive System

Abstract

Digestive system neuroendocrine carcinomas (NECs) are rare neoplasms originating from neuroendocrine cells with a poor prognosis and limited effective treatments. Programmed cell death protein 1/ligand 1 (PD-1/PD-L1) blockade has been used in the management of more than 10 solid tumors and has achieved promising clinical outcomes. PD-L1 expression, immune cell infiltration, tumor mutational burden (TMB), and microsatellite instability (MSI) are all verified biomarkers that can predict the response to anti-PD-1/PD-L1 therapy. Here, we investigated PD-L1 expression and immune cell infiltration density by immunohistochemical (IHC) staining of tumor samples from 33 patients with digestive system NECs. Tumor and paratumor normal samples from 31 of these patients underwent whole-exome sequencing to evaluate TMB and the MSI-high (MSI-H) status. In total, 29.0% of digestive system NECs had positive PD-L1 expression according to the tumor proportion score (TPS). Infiltration of CD3 + , CD8 + , and CD68 + cells was observed in 69.7, 27.3, and 54.5% of patients, respectively. The TMB value for patients sequenced ranged from 0.57 to 11.75 mutations/Mb, with a median of 5.68 mutations/Mb. mSINGS, MSIsensor, and MSIseq were used to analyze the MSI status according to the sequencing data, and in our evaluation, no MSI-H status was detected. Our data might indicate a limited potential of anti-PD-1/PD-L1 monotherapy in digestive system NECs, although clinical trials are warranted.

CD3+, CD8+, CD4+ and FOXP3+ T Cells in the Immune Microenvironment of Small Bowel Neuroendocrine Tumors

“…They found no difference in overall survival between different densities of CD3 + or CD8 + T cells. Contrary to our finding, Xing et al found some tumors lacking T cell infiltrates [ 20 ]. This may be due to underlying biological differences between neuroendocrine carcinomas and NETs.…”

“…That study reported no clear association between T cell densities and survival. A study by Xing et al analyzed the inflammation in 33 neuroendocrine carcinomas of the digestive tract by semiquantitative scores based on percentages of staining cell infiltration of the stromal area (low infiltration was 0–25% staining and high infiltration >25% staining) [ 20 ]. They found intratumoral CD3 + T cell infiltration in 69.7% of patients and CD8 + T cell infiltration in 27.3%.…”

PD-L1 expression and patient outcomes in gastrointestinal neuroendocrine neoplasm: a meta-analysis

“…Further, all studies had relatively high quality, with NOS of 7. Seven studies were analyzed for the correlation between PD-L1 expression and sex (Figure 2B) (11,(13)(14)(15)(16)(17)(18). In total, 134 of the 339 male patients were PD-L1 positive, whereas 59 of the 185 female patients were PD-L1 positive.…”

“…GEP-NEN, gastroenteropancreatic-neuroendocrine neoplasia; NET, neuroendocrine tumor; SCC, small cell carcinoma; NEC, neuroendocrine carcinoma; N/A, not available. Three studies were analyzed for the association between tumor stage and PD-L1 expression (Figure 2E) (13,16,17). Of the 120 stage I/II cases and 109 stage III/IV cases, 47 and 67 cases, respectively, were PD-L1 positive.…”

“…Increasing research on PD-L1 expression and its prognostic and clinicopathological value have in turn led to expanding application of PD-L1 inhibitors (7,8). In gastrointestinal NENs, several studies have reported that PD-L1 expression is associated with survival and clinicopathological parameters (9)(10)(11)(12)(13)(14)(15)(16)(17)(18). However, these studies were relatively small scale.…”