Published online Oct 28, 2023. doi: 10.3748/wjg.v29.i40.5566
Peer-review started: August 14, 2023
First decision: September 19, 2023
Revised: October 4, 2023
Accepted: October 23, 2023
Article in press: October 23, 2023
Published online: October 28, 2023
According to a recent report from the United States, the incidence of small bowel adenocarcinoma (SBA) has been increasing, with an annual increase of 1.8% between 2006 and 2015. Comprehensive genomic analyses revealed that SBA and colorectal cancer have different genomic profiles, and it is assumed that the molecular pathways leading to carcinogenesis may also be different. Therefore, it is essential to establish chemotherapeutic regimens based on the specific characteristics of SBA.
The clinicopathological significance of programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 (PD-L2) expression in SBA is not yet fully understood. There are several conflicting reports regarding the clinicopathological significance of PD-L1 expression in gastrointestinal cancers. To resolve this discrepancy, we investigated the clinical significance of PD-L1 and PD-L2 expression according to tumor microenvironment (TME) status stratified by the density of FoxP3+ and CD8+ T cells.
In this study, we investigated the clinicopathological significance of PD-L1 and PD-L2 expression in association with the infiltration of FoxP3+ and CD8+ T cells in the TME to identify PD-L/PD-1 immunotherapy candidates among patients with SBA. We elucidated the discrepancy in previously reported clinical significance of PD-L1 expression in SBA.
The immunoreactivities of PD-L1 and PD-L2 were determined separately in tumor cells and tumor-infiltrating immune cells, such as lymphocytes and macrophages, and evaluated using the combined positive score (CPS). To our knowledge, this is the first study to examine the relationship between PD-L2 expression, and the density of FoxP3+ T cells, and the clinicopathological characteristics of patients with SBA.
PD-L1 expression was positive in 34% in tumor cells (T-PD-L1) and 54% in tumor-infiltrating immune cells (I-PD-L1) of the cases examined. T-PD-L2 was positive in 34% and I-PD-L2 was positive in 42% of the cases, respectively. PD-L1 CPS ≥ 10 and PD-L2 CPS ≥ 10 were observed in 50% and 56% of cases, respectively. I-PD-L1 and I-PD-L2 Levels were significantly associated with better prognosis. We speculated that I-PD-L1 expression might be influenced by peritumoral infiltrating T cells, which correlates with favorable prognosis. We found that patients with PD-L2 CPS ≥ 10 tended to have worse prognosis in the FoxP3/CD8-low group. Although SBA patients with high immune cell infiltration, such as those in the FoxP3/CD8-low group, generally have better prognosis, some have poorer prognosis. Therefore, PD-L2 may contribute to the poor prognosis of these patients.
We identified a discrepancy in the previously reported clinical significance of PD-L1 expression in SBA. Several studies have reported that PD-L1 expression, which is involved in tumorigenesis, is associated with favorable prognosis. This contradictory finding may originate from the fact that all patients were equally included in the analysis without considering the TME status and the type of cells in which PD-L1 was expressed. To identify PD-L/PD-1 immunotherapy candidates, not only PD-L1 expression and DNA mismatch repair/microsatellite instability but also PD-L2 expression and the density of tumor-infiltrating lymphocytes, such as FoxP3+ and CD8+ T cells, in the TME should be considered.
In this study, we did not consider tumor mutation burden (TMB). TMB-high has been proposed as a predictive biomarker for the response to immune checkpoint inhibitors based on the assumption that increasing the number of mutant proteins will create antigenic peptides, allowing for enhanced immunogenicity. In the future, we may be able to analyze TMB status in SBA and combine it with PD-L1/2 expression and TME status to generate powerful biomarkers for identifying immunotherapy candidates.