Introduction: Immune checkpoint inhibitors provide new treatments for patients with recurrent or metastatic (R/M) head and neck cancers. Herein, we focused on systemic inflammatory markers in peripheral blood, including blood cell fractions, albumin (Alb), and C-reactive protein, and determined their association with nivolumab treatment response. We also examined the potential application of inflammatory markers as prognostic tools. Methods: We assessed pretreatment systemic inflammatory markers in 61 patients with R/M head and neck cancer treated with nivolumab, determining their association with treatment response using Kaplan-Meier, multivariate, and regression analyses. Using flow cytometry, we investigated circulating T-cell subsets in 36 patients with R/M head and neck cancer. Finally, we examined the correlation between each statistically analyzed parameter and peripheral circulating T-cell activation. Results: Systemic inflammatory marker values were used to estimate overall survival (OS) time by performing multivariate analysis. Systemic inflammatory markers were assigned importance for each coefficient. Monocyte and lymphocyte counts strongly impacted OS. Indices dependent on white blood cell and monocyte counts, lymphocyte percentage, platelet count, Alb levels, and prognostic nutrition index were useful prognostic tools in the regression analysis. The simplest prognostic index was defined as white blood cells (103/μL) +2 × lymphocyte percentage (%) +12 × number of monocytes (103/μL) + 27 × serum Alb. A high index that was significantly associated with a better prognosis negatively correlated with CD38/CD8 and ki67/CD8 percentages. Conclusions: According to the findings of the present study, systemic inflammatory markers may help predict the prognosis, activation, and exhaustion of circulating T cells. In patients with R/M head and neck cancer treated with nivolumab, systemic inflammatory markers could provide new insights into rational strategies in cancer immunotherapy for R/M head and neck cancer.

1.
Tada
H
,
Takahashi
H
,
Yamada
K
,
Masuda
K
,
Nagata
Y
,
Uchida
M
, et al
.
Dynamic alterations of circulating T lymphocytes and the clinical response in patients with head and neck squamous cell carcinoma treated with nivolumab
.
Cancer Immunol Immunother
.
2022
;
71
(
4
):
851
63
.
2.
Mantovani
A
,
Allavena
P
,
Sica
A
,
Balkwill
F
.
Cancer-related inflammation
.
Nature
.
2008
;
454
(
7203
):
436
44
.
3.
Sumner
WA
,
Stokes
WA
,
Oweida
A
,
Berggren
KL
,
McDermott
JD
,
Raben
D
, et al
.
Survival impact of pre-treatment neutrophils on oropharyngeal and laryngeal cancer patients undergoing definitive radiotherapy
.
J Transl Med
.
2017
;
15
(
1
):
168
.
4.
Nakahira
M
,
Sugasawa
M
,
Matsumura
S
,
Kuba
K
,
Ohba
S
,
Hayashi
T
, et al
.
Prognostic role of the combination of platelet count and neutrophil-lymphocyte ratio in patients with hypopharyngeal squamous cell carcinoma
.
Eur Arch Oto-Rhino-Laryngol
.
2016
;
273
(
11
):
3863
7
.
5.
Nakashima
H
,
Matsuoka
Y
,
Yoshida
R
,
Nagata
M
,
Hirosue
A
,
Kawahara
K
, et al
.
Pre-treatment neutrophil to lymphocyte ratio predicts the chemoradiotherapy outcome and survival in patients with oral squamous cell carcinoma: a retrospective study
.
BMC Cancer
.
2016
;
16
:
41
.
6.
Charles
KA
,
Harris
BDW
,
Haddad
CR
,
Clarke
SJ
,
Guminski
A
,
Stevens
M
, et al
.
Systemic inflammation is an independent predictive marker of clinical outcomes in mucosal squamous cell carcinoma of the head and neck in oropharyngeal and non-oropharyngeal patients
.
BMC Cancer
.
2016
;
16
:
124
.
7.
Ozturk
K
,
Akyildiz
NS
,
Uslu
M
,
Gode
S
,
Uluoz
U
.
The effect of preoperative neutrophil, platelet and lymphocyte counts on local recurrence and survival in early-stage tongue cancer
.
Eur Arch Oto-Rhino-Laryngol
.
2016
;
273
(
12
):
4425
9
.
8.
Fang
HY
,
Huang
XY
,
Chien
HT
,
Chang
JTC
,
Liao
CT
,
Huang
JJ
, et al
.
Refining the role of preoperative C-reactive protein by neutrophil/lymphocyte ratio in oral cavity squamous cell carcinoma
.
Laryngoscope
.
2013
;
123
(
11
):
2690
9
.
9.
Chu
J
,
Sun
N
,
Hu
W
,
Chen
X
,
Yi
N
,
Shen
Y
.
Bayesian hierarchical lasso Cox model: a 9-gene prognostic signature for overall survival in gastric cancer in an Asian population
.
PLoS One
.
2022
;
17
(
4
):
e0266805
.
10.
Chen
Y
,
Wen
S
,
Xia
J
,
Du
X
,
Wu
Y
,
Pan
B
, et al
.
Association of dynamic changes in peripheral blood indexes with response to PD-1 inhibitor-based combination therapy and survival among patients with advanced non-small cell lung cancer
.
Front Immunol
.
2021
;
12
:
672271
.
11.
Fukui
T
,
Okuma
Y
,
Nakahara
Y
,
Otani
S
,
Igawa
S
,
Katagiri
M
, et al
.
Activity of nivolumab and utility of neutrophil-to-lymphocyte ratio as a predictive biomarker for advanced non-small-cell lung cancer: a prospective observational study
.
Clin Lung Cancer
.
2019
;
20
(
3
):
208
14.e2
.
12.
Qu
Z
,
Wang
Q
,
Wang
H
,
Jiao
Y
,
Li
M
,
Wei
W
, et al
.
The effect of inflammatory markers on the survival of advanced gastric cancer patients who underwent anti-programmed death 1 therapy
.
Front Oncol
.
2022
;
12
:
783197
.
13.
Sakai
A
,
Iijima
H
,
Ebisumoto
K
,
Yamauchi
M
,
Teramura
T
,
Yamazaki
A
, et al
.
Prognostic value of inflammatory and nutritional biomarkers of immune checkpoint inhibitor treatment for recurrent or metastatic squamous cell carcinoma of the head and neck
.
Cancers
.
2023
;
15
(
7
):
2021
.
14.
Arihara
Y
,
Takada
K
,
Murase
K
,
Kawamura
K
,
Kakiuchi
A
,
Kurose
M
, et al
.
Inflammation and malnutrition as markers of poor outcomes in head and neck cancer patients treated with nivolumab
.
Acta Otolaryngol
.
2023
;
143
(
8
):
714
20
.
15.
Ueda
T
,
Chikuie
N
,
Takumida
M
,
Furuie
H
,
Kono
T
,
Taruya
T
, et al
.
Baseline neutrophil-to-lymphocyte ratio (NLR) is associated with clinical outcome in recurrent or metastatic head and neck cancer patients treated with nivolumab
.
Acta Otolaryngol
.
2020
;
140
(
2
):
181
7
.
16.
Yildirim
HC
,
Kus
F
,
Guven
DC
,
Karaca
E
,
Kaygusuz
Y
,
Dizdar
O
, et al
.
Mean platelet volume to lymphocyte ratio: a new biomarker predicting response in patients with solid tumors treated with nivolumab
.
J Immunother Precis Oncol
.
2023
;
6
(
4
):
170
6
.
17.
Hernando-Calvo
A
,
Mirallas
O
,
Marmolejo
D
,
Saavedra
O
,
Vieito
M
,
Assaf Pastrana
JD
, et al
.
Nutritional status associates with immunotherapy clinical outcomes in recurrent or metastatic head and neck squamous cell carcinoma patients
.
Oral Oncol
.
2023
;
140
:
106364
.
18.
Minohara
K
,
Matoba
T
,
Kawakita
D
,
Takano
G
,
Oguri
K
,
Murashima
A
, et al
.
Novel Prognostic Score for recurrent or metastatic head and neck cancer patients treated with Nivolumab
.
Sci Rep
.
2021
;
11
(
1
):
16992
.
19.
Huai
Q
,
Luo
C
,
Song
P
,
Bie
F
,
Bai
G
,
Li
Y
, et al
.
Peripheral blood inflammatory biomarkers dynamics reflect treatment response and predict prognosis in non-small cell lung cancer patients with neoadjuvant immunotherapy
.
Cancer Sci
.
2023
;
114
(
12
):
4484
98
.
20.
Petrie
HT
,
Klassen
LW
,
Kay
HD
.
Inhibition of human cytotoxic T lymphocyte activity in vitro by autologous peripheral blood granulocytes
.
J Immunol
.
1985
;
134
(
1
):
230
4
.
21.
Lee
YJ
,
Kim
WR
,
Han
J
,
Han
YD
,
Cho
MS
,
Hur
H
, et al
.
Prognostic impact of immunonutritional status changes during preoperative chemoradiation in patients with rectal cancer
.
Ann Coloproctol
.
2016
;
32
(
6
):
208
14
.
22.
Ugel
S
,
Canè
S
,
De Sanctis
F
,
Bronte
V
.
Monocytes in the tumor microenvironment
.
Annu Rev Pathol
.
2021
;
16
:
93
122
.
23.
Peng
L
,
Wang
Y
,
Liu
F
,
Qiu
X
,
Zhang
X
,
Fang
C
, et al
.
Peripheral blood markers predictive of outcome and immune-related adverse events in advanced non-small cell lung cancer treated with PD-1 inhibitors
.
Cancer Immunol Immunother
.
2020
;
69
(
9
):
1813
22
.
24.
Bajaj
G
,
Suryawanshi
S
,
Roy
A
,
Gupta
M
.
Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology
.
Br J Clin Pharmacol
.
2019
;
85
(
9
):
2045
58
.
25.
Dirks
NL
,
Meibohm
B
.
Population pharmacokinetics of therapeutic monoclonal antibodies
.
Clin Pharmacokinet
.
2010
;
49
(
10
):
633
59
.
26.
Zheng
M
.
Serum albumin: a pharmacokinetic marker for optimizing treatment outcome of immune checkpoint blockade
.
J Immunother Cancer
.
2022
;
10
(
12
):
e005670
.
27.
Xiong
H
,
Mittman
S
,
Rodriguez
R
,
Moskalenko
M
,
Pacheco-Sanchez
P
,
Yang
Y
, et al
.
Anti-PD-L1 treatment results in functional remodeling of the macrophage compartment
.
Cancer Res
.
2019
;
79
(
7
):
1493
506
.
28.
Schetters
STT
,
Rodriguez
E
,
Kruijssen
LJW
,
Crommentuijn
MHW
,
Boon
L
,
Van den Bossche
J
, et al
.
Monocyte-derived APCs are central to the response of PD1 checkpoint blockade and provide a therapeutic target for combination therapy
.
J Immunother Cancer
.
2020
;
8
(
2
):
e000588
.
29.
Eissler
N
,
Mao
Y
,
Brodin
D
,
Reuterswärd
P
,
Andersson Svahn
H
,
Johnsen
JI
, et al
.
Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade
.
Oncoimmunology
.
2016
;
5
(
12
):
e1232222
.
30.
Zitvogel
L
,
Kepp
O
,
Kroemer
G
.
Immune parameters affecting the efficacy of chemotherapeutic regimens
.
Nat Rev Clin Oncol
.
2011
;
8
(
3
):
151
60
.
31.
Wu
P
,
Zhao
L
,
Chen
Y
,
Xin
Z
,
Lin
M
,
Hao
Z
, et al
.
CD38 identifies pre-activated CD8+ T cells which can be reinvigorated by anti-PD-1 blockade in human lung cancer
.
Cancer Immunol Immunother
.
2021
;
70
(
12
):
3603
16
.
32.
Yost
KE
,
Satpathy
AT
,
Wells
DK
,
Qi
Y
,
Wang
C
,
Kageyama
R
, et al
.
Clonal replacement of tumor-specific T cells following PD-1 blockade
.
Nat Med
.
2019
;
25
(
8
):
1251
9
.
33.
Zhang
N
,
Bevan
MJ
.
CD8(+) T cells: foot soldiers of the immune system
.
Immunity
.
2011
;
35
(
2
):
161
8
.
34.
Chen
PY
,
Wu
CYJ
,
Fang
JH
,
Chen
HC
,
Feng
LY
,
Huang
CY
, et al
.
Functional change of effector tumor-infiltrating CCR5+CD38+HLA-DR+CD8+ T cells in glioma microenvironment
.
Front Immunol
.
2019
;
10
:
2395
.
35.
Takahashi
H
,
Sakakura
K
,
Ida
S
,
Kawabata-Iwakawa
R
,
Matsuyama
T
,
Tada
H
, et al
.
Circulating naïve and effector memory T cells correlate with prognosis in head and neck squamous cell carcinoma
.
Cancer Sci
.
2022
;
113
(
1
):
53
64
.
36.
Blessin
NC
,
Li
W
,
Mandelkow
T
,
Jansen
HL
,
Yang
C
,
Raedler
JB
, et al
.
Prognostic role of proliferating CD8+ cytotoxic Tcells in human cancers
.
Cell Oncol
.
2021
;
44
(
4
):
793
803
.
37.
Huang
AC
,
Postow
MA
,
Orlowski
RJ
,
Mick
R
,
Bengsch
B
,
Manne
S
, et al
.
T-cell invigoration to tumour burden ratio associated with anti-PD-1 response
.
Nature
.
2017
;
545
(
7652
):
60
5
.
38.
Simoni
Y
,
Becht
E
,
Fehlings
M
,
Loh
CY
,
Koo
SL
,
Teng
KWW
, et al
.
Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates
.
Nature
.
2018
;
557
(
7706
):
575
9
.
39.
Blessin
NC
,
Abu-Hashem
R
,
Mandelkow
T
,
Li
W
,
Simon
R
,
Hube-Magg
C
, et al
.
Prevalence of proliferating CD8+ cells in normal lymphatic tissues, inflammation and cancer
.
Aging
.
2021
;
13
(
11
):
14590
603
.
40.
Ruiz-Ranz
M
,
Lequerica-Fernández
P
,
Rodríguez-Santamarta
T
,
Suárez-Sánchez
FJ
,
López-Pintor
RM
,
García-Pedrero
JM
, et al
.
Prognostic implications of preoperative systemic inflammatory markers in oral squamous cell carcinoma, and correlations with the local immune tumor microenvironment
.
Front Immunol
.
2022
;
13
:
941351
.
You do not currently have access to this content.