Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a catastrophic malignancy of the intrahepatic bile ducts and one of the neoplasms with incidence rates that have been rising faster than almost any other cancer. This steady increase combined with the high mortality rates underscore the fact that optimal management of iCCA remains a challenge. While immune checkpoint inhibitors (ICIs) as single agents have elicited discouraging results in patients with iCCA, the combination of chemotherapy plus anti-PD-L1 blockade has recently become the new standard of care, underscoring the importance of designing rational combination strategies able to increase the therapeutic efficacy of ICIs. To do so, a thorough understanding of the tumor-immune interactions is becoming critical. This commentary aims to discuss recent advancements in our understanding of the complex relationship between tumor cells and the surrounding immune microenvironment of iCCA, with particular emphasis on our recent manuscript published in the journal Gut (Martin-serrano et al., 2022) [1].
Commentary
Figure 1: A novel immune microenvironment-based classification of iCCA. The STIM classification is based on the integrative analysis of genomic, transcriptomic and immunophenotypic analysis of a large cohort of human iCCA samples. Characteristics of each class are indicated. Potential therapeutic opportunities include small-molecule inhibitor and immunotherapy combinations targeting characteristics of specific tumor profiles. BAP1: BRCA1-Associated Protein 1; CDKi: Cyclin Dependent Kinase inhibitor; CNV: Chromosomal Number Variation; FGFR: Fibroblast Growth Factor Receptor; IDH1/2: Isocitrate Dehydrogenase 1/2; KRAS: Kirsten Rat Sarcoma; TP53: Tumor Protein 53.
Acknowledgments
Figures 1 was created with Biorender.
Disclosure
The authors declare no conflict of interest.
References
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3. Rumgay H, Ferlay J, de Martel C, Georges D, Ibrahim AS, Zheng R, et al. Global, regional and national burden of primary liver cancer by subtype. European Journal of Cancer. 2022 Jan 1;161:108-18.
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7. Sia D, Losic B, Moeini A, Cabellos L, Hao K, Revill K, et al. Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nature communications. 2015 Jan 22;6(1):1-1.
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9. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, et al. Genomic spectra of biliary tract cancer. Nature Genetics. 2015 Sep;47(9):1003-10.
10. Chan-On W, Nairismägi ML, Ong CK, Lim WK, Dima S, Pairojkul C, et al. Exome sequencing identifies distinct mutational patterns in liver fluke–related and non-infection-related bile duct cancers. Nature Genetics. 2013 Dec;45(12):1474-8.
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12. Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, Nakamura H, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology. 2014 Apr;59(4):1427-34.
13. Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discovery. 2013 Jun;3(6):636-47.
14. Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. The Lancet Oncology. 2020 May 1;21(5):671-84.
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16. Makawita S, K Abou-Alfa G, Roychowdhury S, Sadeghi S, Borbath I, Goyal L, et al. Infigratinib in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF 301 trial. Future Oncology. 2020 Oct;16(30):2375-84.
17. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer. 2012 Apr;12(4):252-64.
18. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015 Apr 3;348(6230):56-61.
19. Tang J, Yu JX, Hubbard-Lucey VM, Neftelinov ST, Hodge JP, Lin Y. Trial watch: the clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors. Nature Reviews Drug Discovery. 2018 Dec 1;17(12):854-6.
20. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. New England Journal of Medicine. 2015 Jun 25;372(26):2509-20.
21. Goeppert B, Roessler S, Renner M, Singer S, Mehrabi A, Vogel MN, Pathil A, Czink E, Köhler B, Springfeld C, Pfeiffenberger J. Mismatch repair deficiency is a rare but putative therapeutically relevant finding in non-liver fluke associated cholangiocarcinoma. British journal of cancer. 2019 Jan;120(1):109-14.
22. Isa T, Tomita S, Nakachi A, Miyazato H, Shimoji H, Kusano T, et al. Analysis of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahepatic cholangiocarcinoma. Hepato-Gastroenterology. 2002 May 1;49(45):604-8.
23. Momoi H, Itoh T, Nozaki Y, Arima Y, Okabe H, Satoh S, et al. Microsatellite instability and alternative genetic pathway in intrahepatic cholangiocarcinoma. Journal of Hepatology. 2001 Aug 1;35(2):235-44.
24. Weinberg BA, Xiu J, Lindberg MR, Shields AF, Hwang JJ, Poorman K, et al. Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets. Journal of Gastrointestinal Oncology. 2019 Aug;10(4):652.
25. Piha‐Paul SA, Oh DY, Ueno M, Malka D, Chung HC, Nagrial A, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE‐158 and KEYNOTE‐028 studies. International Journal of Cancer. 2020 Oct 15;147(8):2190-8.
26. Oh DY, Ruth He A, Qin S, Chen LT, Okusaka T, Vogel A, et al. Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM Evidence. 2022 Jun 1:EVIDoa2200015.
27. Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, et al. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Reports. 2017 Jan 3;18(1):248-62.
28. Yang J, Zhao S, Wang J, Sheng Q, Liu Q, Shyr Y. A pan-cancer immunogenomic atlas for immune checkpoint blockade immunotherapy. Cancer Research. 2021 Dec 13.
29. Sia D, Hoshida Y, Villanueva A, Roayaie S, Ferrer J, Tabak B, et al. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology. 2013 Apr 1;144(4):829-40.
30. Andersen JB, Spee B, Blechacz BR, Avital I, Komuta M, Barbour A, et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology. 2012 Apr 1;142(4):1021-31.
31. Job S, Rapoud D, Dos Santos A, Gonzalez P, Desterke C, Pascal G, et al. Identification of four immune subtypes characterized by distinct composition and functions of tumor microenvironment in intrahepatic cholangiocarcinoma. Hepatology. 2020 Sep;72(3):965-81.
32. Zhang M, Yang H, Wan L, Wang Z, Wang H, Ge C, et al. Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma. Journal of Hepatology. 2020 Nov 1;73(5):1118-30.
33. Ma L, Hernandez MO, Zhao Y, Mehta M, Tran B, Kelly M, et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell. 2019 Oct 14;36(4):418-30.
34. Zheng M, Tian Z. Liver-mediated adaptive immune tolerance. Frontiers in Immunology. 2019 Nov 5;10:2525.
35. Wu MJ, Shi L, Dubrot J, Merritt J, Vijay V, Wei TY, et al. Mutant IDH inhibits IFNγ–TET2 signaling to promote immunoevasion and tumor maintenance in cholangiocarcinoma. Cancer Discovery. 2022 Mar 1;12(3):812-35.
36. Lin Y, Peng L, Dong L, Liu D, Ma J, Lin J, et al. Geospatial Immune Heterogeneity Reflects the Diverse Tumor–Immune Interactions in Intrahepatic Cholangiocarcinoma. Cancer Discovery. 2022 Oct 5;12(10):2350-71.
37. Akhand SS, Liu Z, Purdy SC, Abdullah A, Lin H, Cresswell GM, et al. Pharmacologic inhibition of FGFR modulates the metastatic immune microenvironment and promotes response to immune checkpoint blockade. Cancer Immunology Research. 2020 Dec;8(12):1542-53.
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