HCC immunology: correlating immune profiles to specific response to immunotherapy
Gastroenterology
Final Report Abstract
The initial research plan focused on exploring the immune landscape of HCC and its implications for treatment with immune checkpoint inhibitors in HCC. We established a wellannotated clinical cohort of 240 patients with RNA-, Whole-exome- and TCR sequencing data as well as comprehensive immunophenotyping via single- and multiplex immunostaining. Integrative analysis refined our understanding of the immune-based molecular classes. We defined five distinct subclasses, three of those representing immunogenic tumors and accounting for ~35% of the population and two representing non-inflamed tumors that harbor distinct mechanisms of immune evasion. When we applied these findings to a cohort of patients treated with anti-PD1 we found inflamed tumors to be more likely to exhibit response to therapy. Overall responding patients were characterized by active inflammatory signaling as captured by an increase in IFNy signaling and an intact antigen-presentation machinery with strong expression of MHC class II molecules. We developed a gene expression signature capable of reliably identifying responding patients and validated it in four publically available datasets. Of note, none of the previously reported signatures of response that derive from other cancer types were able to consistently distinguish between responders and nonresponders. Intriguingly, we observed that treatment with tyrosine-kinase inhibitors, until recently standard of care in frontline treatment of advanced HCC, appeared to modulate response patterns to subsequent immunotherapy. These findings have implications for clinical practice: as the treatment landscape of HCC evolves, biomarker discovery is likely to hinge on the acquisition of fresh biological samples prior to the initiation of a given systemic treatment. Our findings support the implementation of serial biopsies in clinical practice for patients with advanced HCC.
Publications
- Liver transplant for hepatocellular carcinoma in the United States: Evolving trends over the last three decades. Am J Transplant. 2020 Jan;20(1):220-230
Marc Puigvehi, Dana Hashim, Philipp K Haber, Amreen Dinani, Thomas D Schiano, Amon Asgharpour, Tatyana Kushner, Gaurav Kakked, Parissa Tabrizian, Myron Schwartz, Ahmet Gurakar, Douglas Dieterich, Paolo Boffetta, Scott L Friedman, Josep M Llovet, Behnam Saberi
(See online at https://doi.org/10.1111/ajt.15576) - Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021 Jan 28
Llovet JM, De Baere T, Kulik L, Haber PK, Greten TF, Meyer T, Lencioni R
(See online at https://doi.org/10.1038/s41575-020-00395-0) - Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene. 2021 Jan;40(1):140-151
von Felden J, Craig AJ, Garcia-Lezana T, Labgaa I, Haber PK, D'Avola D, Asgharpour A, Dieterich D, Bonaccorso A, Torres-Martin M, Sia D, Sung MW, Tabrizian P, Schwartz M, Llovet JM, Villanueva A
(See online at https://doi.org/10.1038/s41388-020-01519-1) - NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021 Mar 24
Pfister D, ..., Heikenwalder M
(See online at https://doi.org/10.1038/s41586-021-03362-0)
