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. 2025 Nov 4:gutjnl-2025-334861.
doi: 10.1136/gutjnl-2025-334861. Online ahead of print.

Immunosuppressive contribution of tumour-infiltrating B cells in human intrahepatic cholangiocarcinoma and their role in chemoimmunotherapy outcome

Giulia Milardi  1 , Barbara Franceschini  1 , Chiara Camisaschi  2 , Simone Puccio  3   4 , Guido Costa  5   6 , Cristiana Soldani  1 , Paolo Uva  7 , Davide Cangelosi  7 , Roberta Carriero  8 , Luca Lambroia  8 , Antonella Cammarota  1   6 , Giulio Lodetti-Zangrandi  1 , Ines Malenica  4 , Marco Erreni  6   9 , Ilaria Montali  2 , Tiziano Lottini  10 , Chiara Raggi  10 , Paolo Kunderfranco  8 , Michela Anna Polidoro  1 , Alessio Aghemo  6   11 , Rita Balsano  6   12 , Tiziana Pressiani  12 , Salvatore Piscuoglio  6   13 , Luca Di Tommaso  6   13 , Guido Torzilli  5   6 , Lorenza Rimassa  6   12 , Enrico Lugli  4 , Barbara Cassani  14   15 , Ana Lleo  16   11
Affiliations
Free article

Immunosuppressive contribution of tumour-infiltrating B cells in human intrahepatic cholangiocarcinoma and their role in chemoimmunotherapy outcome

Giulia Milardi et al. Gut. .
Free article

Abstract

Background: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive biliary tract cancer with a poor prognosis and a complex tumour microenvironment (TME) that remains poorly understood.

Objective: This study aimed to investigate the phenotypic and molecular characteristics of B lymphocytes, their interactions with the TME and their prognostic implications.

Design: B-cell compartments in the tumour, peritumour, and peripheral blood of iCCA patients were analysed using multimodal single-cell technologies. The B-cell interactome with the iCCA TME was explored in silico, and ex vivo assays assessed the impact of interactions with cancer-associated fibroblasts (CAFs) and tumour cells on B-cell biology. B-cell modulation during chemoimmunotherapy in advanced iCCA was also evaluated.

Results: B cells were enriched in adjacent tumour-free tissues and formed mature tertiary lymphoid structures (TLS), correlating with better prognosis. Conversely, tumour-infiltrating B cells were scarce, immature and displayed reduced effector function with increased immunosuppressive features. Coculture with tumour cells or CAFs impaired B-cell differentiation and function, including downregulation of BAFFR in peripheral B cells. IL-6 and TGF-β emerged as major drivers of B-cell dysfunction; dual blockade restored B-cell activation and differentiation. Elevated frequencies of circulating BAFFR+ B cells and hyperexpanded clonotypes were linked to improved chemoimmunotherapy response.

Conclusions: iCCA is characterised by a profoundly immunosuppressive TME that impairs B-cell function through soluble factors and cellular interactions. Our findings identify B cells as biomarkers and therapeutic targets, supporting strategies to restore B-cell function and promote mature TLS to enhance immunotherapy responsiveness in iCCA.

Keywords: CANCER IMMUNOBIOLOGY; HEPATOBILIARY CANCER; IMMUNOTHERAPY; LIVER.

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Conflict of interest statement

Competing interests: AL has received consulting fees from Advanz Pharma, GSK, Ipsen, Gilead, Dr Falk, AlfaSigma and Takeda, speaker fees from Gilead, AbbVie, MSD, Advanz Pharma, AlfaSigma, GSK, AstraZeneca, Ipsen and Incyte. She has received travel support from Ipsen and Falk Foundation and grant support (to Humanitas Research Hospital) from Mirum, GSK, Ipsen, Dr Falk, Gilead. LR has received consulting fees from AbbVie, AstraZeneca, Basilea, Bayer, BMS, Eisai, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; speaker fees from AstraZeneca, Bayer, BMS, Guerbet, Incyte, Ipsen, Roche, Servier; travel expenses from AstraZeneca; research funding to Humanitas Research Hospital from AbbVie, Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Jazz Pharmaceuticals, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, TransThera Sciences, Zymeworks. TP received/reports consulting fees from Bayer, Ipsen and AstraZeneca; institutional research funding from Roche, Bayer, AstraZeneca; support for congress attendance from Roche. EL is listed as the inventor on a patent on TSCM cells and received royalties related to that patent, received research funding from Bristol Myers Squibb on a topic unrelated to this paper and reports consulting fees from BD Biosciences, BioLegend, Swarm Oncology, Pfizer, Menarini and AstraZeneca. All the other authors have nothing to declare.

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