Immunotherapy response induces divergent tertiary lymphoid structure morphologies in hepatocellular carcinoma

Daniel H Shu^{1

2

3}, Won Jin Ho^{2

3}, Luciane T Kagohara^{2

3}, Alexander Girgis^{2

3

4}, Sarah M Shin², Ludmila Danilova², Jae W Lee⁵, Dimitrios N Sidiropoulos^{2

3}, Sarah Mitchell², Kabeer Munjal², Kathryn Howe², Kayla J Bendinelli², Emma Kartalia², Hanfei Qi², Guanglan Mo², Janelle Montagne^{2

3}, James M Leatherman², Tamara Y Lopez-Vidal^{2

3}, Qingfeng Zhu^{3

5}, Amanda L Huff^{2

3}, Xuan Yuan⁴, Alexei Hernandez², Erin M Coyne², Neeha Zaidi^{2

3}, Daniel J Zabransky^{2

3}, Logan L Engle^{6

7

8}, Aleksandra Ogurtsova^{6

7

8}, Marina Baretti², Daniel Laheru^{2

3}, Jennifer N Durham², Hao Wang², Joel C Sunshine^{4

5

6

7

8}, Robert J Johnston⁹, Julie Stein Deutsch^{6

7

8}, Janis M Taube^{6

7

8}, Robert A Anders^{3

5}, Elizabeth M Jaffee^{2

3

8}, Elana J Fertig^{10

11

12

13}, Mark Yarchoan^{14

15

16}

Affiliations

¹ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA.
² Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
³ Convergence Institute, Johns Hopkins University, Baltimore, MD, USA.
⁴ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁵ Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁶ Department of Dermatology, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁷ The Mark Foundation Center for Advanced Genomics and Imaging, Johns Hopkins University, Baltimore, MD, USA.
⁸ Bloomberg∼Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
⁹ Genentech Inc, South San Francisco, CA, USA.
¹⁰ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA. ejfertig@jhmi.edu.
¹¹ Convergence Institute, Johns Hopkins University, Baltimore, MD, USA. ejfertig@jhmi.edu.
¹² Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA. ejfertig@jhmi.edu.
¹³ Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA. ejfertig@jhmi.edu.
¹⁴ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA. mark.yarchoan@jhmi.edu.
¹⁵ Convergence Institute, Johns Hopkins University, Baltimore, MD, USA. mark.yarchoan@jhmi.edu.
¹⁶ Bloomberg∼Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. mark.yarchoan@jhmi.edu.

PMID: 39455893
PMCID: PMC12042221 (available on 2025-11-01)
DOI: 10.1038/s41590-024-01992-w

Immunotherapy response induces divergent tertiary lymphoid structure morphologies in hepatocellular carcinoma

Daniel H Shu et al. Nat Immunol. 2024 Nov.

. 2024 Nov;25(11):2110-2123.

doi: 10.1038/s41590-024-01992-w. Epub 2024 Oct 25.

Authors

Affiliations

¹ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA.
² Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
³ Convergence Institute, Johns Hopkins University, Baltimore, MD, USA.
⁴ Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁵ Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁶ Department of Dermatology, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
⁷ The Mark Foundation Center for Advanced Genomics and Imaging, Johns Hopkins University, Baltimore, MD, USA.
⁸ Bloomberg∼Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
⁹ Genentech Inc, South San Francisco, CA, USA.
¹⁰ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA. ejfertig@jhmi.edu.
¹¹ Convergence Institute, Johns Hopkins University, Baltimore, MD, USA. ejfertig@jhmi.edu.
¹² Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA. ejfertig@jhmi.edu.
¹³ Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA. ejfertig@jhmi.edu.
¹⁴ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA. mark.yarchoan@jhmi.edu.
¹⁵ Convergence Institute, Johns Hopkins University, Baltimore, MD, USA. mark.yarchoan@jhmi.edu.
¹⁶ Bloomberg∼Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. mark.yarchoan@jhmi.edu.

PMID: 39455893
PMCID: PMC12042221 (available on 2025-11-01)
DOI: 10.1038/s41590-024-01992-w

Abstract

Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade, but understanding of the prognostic and predictive value of TLS and the circumstances of their resolution is incomplete. Here we show that in hepatocellular carcinoma treated with neoadjuvant immunotherapy, high intratumoral TLS density at the time of surgery is associated with pathologic response and improved relapse-free survival. In areas of tumor regression, we identify a noncanonical involuted morphology of TLS marked by dispersion of the B cell follicle, persistence of a T cell zone enriched for T cell-mature dendritic cell interactions and increased expression of T cell memory markers. Collectively, these data suggest that TLS can serve as both a prognostic and predictive marker of response to immunotherapy in hepatocellular carcinoma and that late-stage TLS may support T cell memory formation after elimination of a viable tumor.

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Conflict of interest statement

Competing interests

M.Y. reports consulting fees from Astra Zeneca, Exelixis, Genentech, Replimune, Hepion, Lantheus; research funding (to Johns Hopkins) from Bristol-Myers Squibb, Exelixis, Incyte and Genentech; and is a co-founder with equity of Adventris Pharmaceuticals. E.J.F. is on the Scientific Advisory Board of Viosera/Resistance Bio, is a paid consultant for Merck and Mestag Therapeutics, and receives research funds from Abbvie. W.J.H. has received patent royalties from Rodeo/Amgen and is the recipient of grants from Sanofi, NeoTX, and CirclePharma. He has received speaking/travel honoraria from Exelixis and Standard BioTools. E.M.J. reports grant/research support from the Lustgarten Foundation, Break Through Cancer, Roche/Genentech, Bristol-Meyers Squibb; honoraria from Achilles, DragonFly, Parker Institute, Cancer Prevention and Research Institute of Texas, Surge, HDT Bio, Mestag Therapeutics, Medical Home Group; and equity in AbMeta Therapeutics and Adventris Pharmaceuticals. D.J.Z. reports grant/research support from Roche/Genentech. R.J.J. is an employee and stockholder of Roche/Genentech. J.M.T. reports research funding from BMS and Akoya Biosciences; serves as a consultant for BMS, Merck, Astra Zeneca, Genentech, Regeneron, Elephas, Lunaphore, Compugen, and Akoya Biosciences; and holds stock in Akoya Biosciences. The remaining authors declare no competing interests.

References

1. Chalabi M et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 26, 566–576 (2020). - PubMed
1. Ho WJ et al. Neoadjuvant cabozantinib and nivolumab convert locally advanced hepatocellular carcinoma into resectable disease with enhanced antitumor immunity. Nat. Cancer 10.1038/s43018-021-00234-4 (2021). - DOI - PMC - PubMed
1. Cabrita R et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020). - PubMed
1. Helmink BA et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020). - PMC - PubMed
1. Petitprez F et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020). - PubMed

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Immunotherapy response induces divergent tertiary lymphoid structure morphologies in hepatocellular carcinoma

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Immunotherapy response induces divergent tertiary lymphoid structure morphologies in hepatocellular carcinoma

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