PD-L1 expression in pancreaticobiliary adenosquamous carcinoma: a potential biomarker for immunotherapy

Dr. Ward and colleagues described a very interesting study evaluating the immunogenic tumor microenvironment in the rare pancreatic and biliary cancers, pancreaticobiliary adenosquamous carcinoma (PB-ASC), published recently in the Journal of Gastrointestinal Oncology (1). Pancreatic and biliary cancers can have different histologies including adenocarcinoma, squamous carcinoma, adenosquamous carcinoma, small cell carcinoma, acinar cell carcinoma, colloid carcinoma, and other rare histologies. Indeed, treating PB-ASC has been challenging due to its resistance to standard chemotherapy and lack of data to support combination with other therapeutic modalities, including immunotherapy. Several studies investigating immunotherapeutic drugs failed to show efficacy outside microsatellite instability-high (MSI-H) in pancreaticobiliary cancers (2). These include trials investigating the role of checkpoint inhibitors, vaccines, oncolytic viruses, peptides, cytokines, and cell therapy modalities. Reports have classified pancreatic cancer into different subtypes based on molecular signatures, including aberrantly differentiated endocrine, exocrine, pancreatic progenitor, squamous, and immunogenic. However, this has not translated to defining specific targeted treatments for each of these histologies or sub-classifications (3). Hence, understanding the cohort of patients who might benefit from immunotherapeutic intervention is quintessential in this burgeoning era of drug development. The authors present a well-described study evaluating the expression of programmed death-ligand 1 (PD-L1) in patients with PB-ASC and pancreaticobiliary adenocarcinoma (PB-AC). This approach can potentially define a specific cohort of patients who might benefit from immunotherapy treatment, specifically since squamous carcinoma historically is immune sensitive. Three subclassifications were established based on the immunogenic tumor microenvironment: immune inflamed (II), immune excluded (IE), and immune desert based on lymphocyte infiltration of the tumor, stroma or parenchyma. Their results show that PB-ASC tumors had a significantly higher PD-L1 expression frequency than PB-AC. PD-L1 expression was mainly in the squamous histology and PD-L1 frequency of expression was high irrespective of the aforementioned immune subclassifications in PB-ASC. In PB-AC, PD-L1 expression were primarily in the II and IE subtypes. The pros of this study are that it introduces a potential treatment approach for this rare and aggressive pancreaticobiliary cancer phenotype, PB-ASC, in addition to potentially identifying the cohort of patients who might benefit from this treatment, those with a high frequency of PD-L1 expression. This study introduced the notion of treating patients with PB-ASC who have high PD-L1 expression with immunotherapy drugs potentially in addition to radiation if the disease is local and vascular endothelial growth factor (VEGF)-targeted drugs, perhaps in a clinical trial setting. The cons of this study are that it is low-powered albeit understandable given the rarity of the disease as well as is retrospective and somewhat descriptive. However, in our opinion, it is well designed, clearly written, and sheds light on a potential treatment approach for an otherwise aggressive and rare cancer, PB-ASC. We congratulate the authors for this effort; this study will help shape treatment approaches for this disease.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-554/coif). The authors have no conflicts of interest to declare.

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References

1. Ward JD, Fowler M, Robledo-Gomez A, et al. PD-L1 expression in pancreaticobiliary adenosquamous carcinoma: a single-institution case series. J Gastrointest Oncol 2024;15:768-79. [Crossref] [PubMed]
2. Babiker HM, Zahid U, Howe CL, et al. Analyzing the efficacy and safety of immunotherapy in pancreatic ductal adenocarcinoma (PDA): A systematic review and meta-analysis. J Clin Oncol 2018;36:512. [Crossref]
3. Ray K. Molecular subtypes of pancreatic cancer. Nat Rev Gastroenterol Hepatol 2016;13:188.