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Drivers and breaks in the cholangiocarcinoma immune microenvironment.

HepatoBiliary Surg Nutr 2022;11(2):320-323 | https://dx.doi.org/10.21037/hbsn-21-572 Clinically effective immune checkpoint inhibitors (ICI) have transformed cancer treatment over the last decade. This progress was built on a foundation of understanding tumor immunology, immune checkpoint biology, and biomarkers for sensitivity to ICI (1). Monoclonal antibodies disrupting the PD-L1/PD-1 axis or CTLA-4 are highly effective in tumors that are primed for an anti-tumor immune response but suppressed by immune checkpoints (1). This is the case for cancer types with abundant neoantigens, such as melanoma and lung cancer, and in tumors regardless of histology that have elevated tumor mutation burden (TMB) or microsatellite instability (MSI) due to mismatch repair deficiency (dMMR). Elevated expression of PD-L1 is a biomarker of immunosuppression and predicts sensitivity to PD-(L)1 blockade in several tumor types, including lung and gastroesophageal cancer. In cholangiocarcinoma (CCA), the immune landscape and factors predicting response to immunotherapy are less well understood (2). CCA generally lacks a high TMB, and MSI-high status is present in less than 5% of cases. Moreover, CCAs have a desmoplastic and immunosuppressive microenvironment (3). Congruently, early clinical trials of PD-1 blockade showed limited response rates in the range of 6–14% in biliary tract cancers (4,5). Combination immunotherapy targeting PD-1 and CTLA-4 yielded a modestly higher response rate of 23% (6). Tumor PD-L1 expression was associated with a higher response rate and PFS in the nivolumab trial (4) while the difference was not statistically significant for pembrolizumab in KEYNOTE-158 (5). This fact underscores the need to profile biomarkers beyond PD-L1 to identify factors that predict response to existing therapies, and to better understand the unique immunobiology of CCA to develop novel immunotherapy strategies. In this context, Carapeto et al. (7) sought to delineate the immunogenomic landscape of CCA by defining spatially-refined, IHC-based profiles of tumor infiltrating lymphocytes , macrophages and mult iple immune checkpoint molecules in a publication in Hepatology. Expression profiles were correlated with genetic drivers, clinical features, and patient survival. A cohort of 96 patients with intrahepatic CCA (iCCA) that underwent resection at a single institution were included to limit clinical heterogeneity and facilitate identification of significant correlations. Notably, only 4% of the tumors evaluated had PD-L1 expression, indicating that this cohort of patients represents those with a low response rate to ICI monotherapy in prior clinical trials (4,5). Sample clustering based on expression of immune cell markers (CD3, CD4, CD8, and CD68) and immune checkpoints (PD1, LAG3, ICOS, OX40, TIM3, and VISTA) identified 4 subgroups. Subgroup 3 had significantly shorter overall survival, and tumors characterized by high PD-1/LAG3 and low CD3/CD4/ICOS expression, particularly in the central tumor, suggesting a “cold” immune microenvironment. Accordingly, immune cells and checkpoint molecule expression were decreased in the tumor center compared to the invasive margin (Figure 1). These findings are consistent with observations in other malignancies including colorectal cancer, where a cold immune microenvironment is a marker of poor prognosis (1). Commentary