Immune Microenvironments in Molecularly Defined CCA Subsets

It is well established that cholangiocarcinoma (CCA) is a heterogeneous cancer that may be organized into distinct subtypes based on the presence of specific genomic alterations, such as IDH1, FGFR2, and KRAS. Although current evidence indicates that immunotherapy-based combinations are a promising treatment approach in CCA, more effective novel combinations are needed to further improve outcomes. Understanding the specific immune microenvironment of genomically defined subsets of CCA may provide new opportunities for therapeutic development in CCA subsets, as discussed by Mark Yarchoan, MD, at the 5th annual CCA Summit meeting.¹

Available evidence indicates that a strong correlation exists between tumor mutational burden (TMB) and immune checkpoint inhibitor response rate between tumor types; the majority (55%) of the differences in overall response rate (ORR) across cancer types may be explained by TMB.² In the multicohort, open-label, phase 2 study of pembrolizumab (KEYNOTE-158), ORR was 29% in the tissue TMB-high group and 6% in the nontissue TMB-high group.³ However, data from the Checkmate-227 trial indicate that TMB is independent of other clinicopathologic features in non–small cell lung cancer.⁴ In particular, TMB and PD-L1 are found to be independent variables in the majority of cancers, including biliary tract cancers (BTCs).⁵ However, TMB and tumor microenvironment (TME) are strong determinants of PD-1 responsiveness, with high TMB and favorable TME associated with response and low TMB and unfavorable TME associated with resistance.^1,5

Genomic and transcriptomic profiling of about 400 BTCs revealed 4 clusters with distinctive immune microenvironments.¹ Cluster 1 predominately associated with TP53, KRAS, and ATM alterations had the most inflamed TME with increased B cells and plasma cells; cluster 2 associated with CDKN2A/B alterations had decreased memory resting CD4 cells; cluster 3 associated with IDH1 alterations had increased activated natural killer cells and M2 macrophages; and cluster 4 associated with FGFR2 rearrangements and BAP1 mutations had low immune infiltration and decreased activated dendritic cells.⁶ Preliminary data using codetection by indexing reveal similar trends (analysis in progress).¹ Preliminary preclinical data with IDH1 mutations recapitulates human data with more M2 macrophages in IDH1-mutated CCA.¹

Dr Yarchoan concluded that these data provide the initial rationale for exploring targeted inhibition of specific drivers to reprogram the tumor-immune microenvironment, in combination with systemic immunotherapy in patients with BTC.¹

Sources:

1. Yarchoan M. Immune microenvironments in molecularly-defined cholangiocarcinoma subsets. Presented at: 5th Annual CCA Summit Meeting, October 19-21, 2023; Scottsdale, AZ.
2. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377:2500-2501.
3. Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353-1365.
4. Hellmann MD, Nathanson T, Rizvi H, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell. 2018;33(5):843-852.
5. Yarchoan M, Albacker AL, Hopkins AC, et al. PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight. 2019;4(6):e126908.
6. Mody K, Jain P, El-Rafai SM, et al. Clinical, genomic, and transcriptomic data profiling of biliary tract cancer reveals subtype-specific immune signatures. JCO Precis Oncol. 2022;6:e2100510.