Abstract
Introduction: Immunomodulating effects of Helicobacter pylori (H. pylori) have been shown to inhibit antitumor immunity. Resistance to immune checkpoint inhibitor (ICI)-based therapies is common among patients with hepatocellular carcinoma (HCC). This study aimed to assess the effect of H. pylori on the outcomes of ICI in patients with HCC. Methods: We conducted a multicenter study in patients with HCC across a broad range of treatments. Patients received either ICI-based combination regimens or sorafenib-based therapy. H. pylori serostatus and virulence factors were determined and correlated with overall survival (OS), progression-free survival (PFS), and safety across the treatment modalities. Results: 180 patients with HCC were included; among these, 64 were treated with ICI-based regimen and 116 with sorafenib-based regimen. In patients treated with ICI, median OS was shorter in H. pylori-positive patients (10.9 months in H. pylori-positive vs. 18.3 months; p = 0.0384). H. pylori positivity was associated with a shorter PFS in ICI recipients (3.9 months vs. 6.8 months, p = 0.0499). In patients treated with sorafenib, median OS was not shorter among H. pylori-positive patients (13.4 months in H. pylori-positive vs. 10.6 months; p = 0.3353). Immune-related adverse events and rates of gastrointestinal bleeding were comparable between H. pylori-positive and -negative patients. Conclusion:H. pylori seropositivity was linked to poorer outcomes in patients with HCC treated with ICI. This association was not observed among patients receiving sorafenib-based therapies.
Journal Section:
Research Article
References
1.
Ribas
A
, Wolchok
JD
. Cancer immunotherapy using checkpoint blockade
. Science
. 2018
;359
(6382
):1350
–5
. 2.
Reiter
FP
, Ben Khaled
N
, Ye
L
, Zhang
C
, Seidensticker
M
, Op den Winkel
M
, et al. Advances in pharmacotherapy of hepatocellular carcinoma: a state of the art review
. Dig Dis
. 2022
;40
(5
):565
–80
. 3.
Finn
RS
, Qin
S
, Ikeda
M
, Galle
PR
, Ducreux
M
, Kim
T-Y
, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma
. N Engl J Med
. 2020
;382
(20
):1894
–905
. 4.
Sharma
P
, Hu-Lieskovan
S
, Wargo
JA
, Ribas
A
. Primary, adaptive, and acquired resistance to cancer immunotherapy
. Cell
. 2017
;168
(4
):707
–23
. 5.
Roessler
D
, Öcal
O
, Philipp
AB
, Markwardt
D
, Munker
S
, Mayerle
J
, et al. Ipilimumab and nivolumab in advanced hepatocellular carcinoma after failure of prior immune checkpoint inhibitor-based combination therapies: a multicenter retrospective study
. J Cancer Res Clin Oncol
. 2023
;149
(7
):3065
–73
. 6.
Oster
P
, Vaillant
L
, Riva
E
, McMillan
B
, Begka
C
, Truntzer
C
, et al. Helicobacter pylori infection has a detrimental impact on the efficacy of cancer immunotherapies
. Gut
. 2022
;71
(3
):457
–66
. 7.
Malfertheiner
P
, Camargo
MC
, El-Omar
E
, Liou
J-M
, Peek
R
, Schulz
C
, et al. Helicobacter pylori infection
. Nat Rev Dis Primers
. 2023
;9
(1
):19
. 8.
Tonneau
M
, Nolin-Lapalme
A
, Kazandjian
S
, Auclin
E
, Panasci
J
, Benlaifaoui
M
, et al. Helicobacter pylori serology is associated with worse overall survival in patients with melanoma treated with immune checkpoint inhibitors
. Oncoimmunology
. 2022
;11
(1
):2096535
. 9.
Ricke
J
, Klümpen
HJ
, Amthauer
H
, Bargellini
I
, Bartenstein
P
, de Toni
EN
, et al. Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma
. J Hepatol
. 2019
;71
(6
):1164
–74
. 10.
Cillo
U
, Vitale
A
, Grigoletto
F
, Farinati
F
, Brolese
A
, Zanus
G
, et al. Prospective validation of the Barcelona clinic liver cancer staging system
. J Hepatol
. 2006
;44
(4
):723
–31
. 11.
European Association for the Study of the Liver
. EASL clinical practice guidelines: management of hepatocellular carcinoma
. J Hepatol
. 2018
;69
(1
):182
–236
. 12.
Öcal
O
, Schütte
K
, Kupčinskas
J
, Morkunas
E
, Jurkeviciute
G
, de Toni
EN
, et al. Baseline Interleukin-6 and -8 predict response and survival in patients with advanced hepatocellular carcinoma treated with sorafenib monotherapy: an exploratory post hoc analysis of the SORAMIC trial
. J Cancer Res Clin Oncol
. 2022
;148
(2
):475
–85
. 13.
von Elm
E
, Altman
DG
, Egger
M
, Pocock
SJ
, Gøtzsche
PC
, Vandenbroucke
JP
, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies
. J Clin Epidemiol
. 2008
;61
(4
):344
–9
. 14.
Abou-Alfa
GK
, Lau
G
, Kudo
M
, Chan
SL
, Kelley
RK
, Furuse
J
, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma
. NEJM Evid
. 2022
;1
(8
):EVIDoa2100070
. 15.
Torre
LA
, Siegel
RL
, Ward
EM
, Jemal
A
. Global cancer incidence and mortality rates and trends: an update
. Cancer Epidemiol Biomarkers Prev
. 2016
;25
(1
):16
–27
. 16.
Ben Khaled
N
, Mörtl
B
, Beier
D
, Reiter
FP
, Pawlowska-Phelan
D
, Teufel
A
, et al. Changing treatment landscape associated with improved survival in advanced hepatocellular carcinoma: a nationwide, population-based study
. Eur J Cancer
. 2023
;192
:113248
. 17.
Blaser
MJ
, Perez-Perez
GI
, Kleanthous
H
, Cover
TL
, Peek
RM
, Chyou
PH
, et al. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach
. Cancer Res
. 1995
;55
(10
):2111
–5
.18.
Che
H
, Xiong
Q
, Ma
J
, Chen
S
, Wu
H
, Xu
H
, et al. Association of Helicobacter pylori infection with survival outcomes in advanced gastric cancer patients treated with immune checkpoint inhibitors
. BMC Cancer
. 2022
;22
(1
):904
. 19.
Magahis
PT
, Maron
SB
, Cowzer
D
, King
S
, Schattner
M
, Janjigian
Y
, et al. Impact of Helicobacter pylori infection status on outcomes among patients with advanced gastric cancer treated with immune checkpoint inhibitors
. J Immunother Cancer
. 2023
;11
(10
):e007699
. 20.
De Toni
EN
, Schlesinger-Raab
A
, Fuchs
M
, Schepp
W
, Ehmer
U
, Geisler
F
, et al. Age independent survival benefit for patients with hepatocellular carcinoma (HCC) without metastases at diagnosis: a population-based study
. Gut
. 2020
;69
(1
):168
–76
. 21.
Bamford
KB
, Fan
XJ
, Crowe
SE
, Leary
JF
, Gourley
WK
, Luthra
G
, et al. Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype
. Gastroenterology
. 1998
;114
(3
):482
–92
. 22.
Goll
R
, Gruber
FXE
, Olsen
T
, Cui
G
, Raschpichler
G
, Buset
M
, et al. Helicobacter pylori stimulates a mixed adaptive immune response with a strong T‐regulatory component in human gastric mucosa
. Helicobacter
. 2007
;12
(3
):185
–92
. 23.
Oertli
M
, Sundquist
M
, Hitzler
I
, Engler
DB
, Arnold
IC
, Reuter
S
, et al. DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection
. J Clin Invest
. 2012
;122
(3
):1082
–96
. 24.
Cook
KW
, Letley
DP
, Ingram
RJ
, Staples
E
, Skjoldmose
H
, Atherton
JC
, et al. CCL20/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa
. Gut
. 2014
;63
(10
):1550
–9
. 25.
Kienesberger
S
, Cox
LM
, Livanos
A
, Zhang
XS
, Chung
J
, Perez-Perez
GI
, et al. Gastric Helicobacter pylori infection affects local and distant microbial populations and host responses
. Cell Rep
. 2016
;14
(6
):1395
–407
. 26.
Frost
F
, Kacprowski
T
, Rühlemann
M
, Bang
C
, Franke
A
, Zimmermann
K
, et al. Helicobacter pylori infection associates with fecal microbiota composition and diversity
. Sci Rep
. 2019
;9
(1
):20100
. 27.
Guo
Y
, Zhang
Y
, Gerhard
M
, Gao
JJ
, Mejias-Luque
R
, Zhang
L
, et al. Effect of Helicobacter pylori on gastrointestinal microbiota: a population-based study in Linqu, a high-risk area of gastric cancer
. Gut
. 2020
;69
(9
):1598
–607
. 28.
Vétizou
M
, Pitt
JM
, Daillère
R
, Lepage
P
, Waldschmitt
N
, Flament
C
, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota
. Science
. 2015
;350
(6264
):1079
–84
. 29.
Gopalakrishnan
V
, Spencer
CN
, Nezi
L
, Reuben
A
, Andrews
MC
, Karpinets
TV
, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients
. Sci
. 2018
;359
(6371
):97
–103
. 30.
Routy
B
, Le Chatelier
E
, Derosa
L
, Duong
CPM
, Alou
MT
, Daillère
R
, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors
. Science
. 2018
;359
(6371
):91
–7
. 31.
Zheng
Y
, Wang
T
, Tu
X
, Huang
Y
, Zhang
H
, Tan
D
, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma
. J Immunother Cancer
. 2019
;7
(1
):193
. 32.
Baruch
EN
, Youngster
I
, Ben-Betzalel
G
, Ortenberg
R
, Lahat
A
, Katz
L
, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients
. Science
. 2021
;371
(6529
):602
–9
. 33.
Vasapolli
R
, Schutte
K
, Schulz
C
, Vital
M
, Schomburg
D
, Pieper
DH
, et al. Analysis of transcriptionally active bacteria throughout the gastrointestinal tract of healthy individuals
. Gastroenterology
. 2019
;157
(4
):1081
–92.e3
. 34.
Bellot
P
, García-Pagán
JC
, Francés
R
, Abraldes
JG
, Navasa
M
, Pérez-Mateo
M
, et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis
. Hepatology
. 2010
;52
(6
):2044
–52
. 35.
Fouts
DE
, Torralba
M
, Nelson
KE
, Brenner
DA
, Schnabl
B
. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease
. J Hepatol
. 2012
;56
(6
):1283
–92
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