Prognostic significance of plasma interleukin-6/-8 in pancreatic cancer patients receiving chemoimmunotherapy.
OBJECTIVE
To investigate the association of plasma levels of interleukin (IL)-6 and -8 with Wilms' tumor 1 (WT1)-specific immune responses and clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDA) treated with dendritic cells (DCs) pulsed with three types of major histocompatibility complex class I and II-restricted WT1 peptides combined with chemotherapy.


METHODS
During the entire treatment period, plasma levels of IL-6 and -8 were analyzed by ELISA. The induction of WT1-specific immune responses was assessed using the WT1 peptide-specific delayed-type hypersensitivity (DTH) test.


RESULTS
Three of 7 patients displayed strong WT1-DTH reactions throughout long-term vaccination with significantly decreased levels of IL-6/-8 after vaccinations compared with the levels prior to treatment. Moreover, overall survival (OS) was significantly longer in PDA patients with low plasma IL-6 levels (< 2 pg/mL) after 5 vaccinations than in patients with high plasma IL-6 levels (≥ 2 pg/mL) (P = 0.025). After disease progression, WT1-DTH reactions decreased severely and were ultimately negative at the terminal stage of cancer. The decreased levels of IL-6/-8 observed throughout long-term vaccination were associated with WT1-specific DTH reactions and long-term OS.


CONCLUSIONS
Prolonged low levels of plasma IL-6/-8 in PDA patients may be a prognostic marker for the clinical outcomes of chemoimmunotherapy.
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Shintaro
S
Tsukinaga
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Mikio
M
Kajihara
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Kazuki
K
Takakura
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Zensho
Z
Ito
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Tomoya
T
Kanai
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Keisuke
K
Saito
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Shinichiro
S
Takami
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Hiroko
H
Kobayashi
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Yoshihiro
Y
Matsumoto
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Shunichi
S
Odahara
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Kan
K
Uchiyama
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Hiroshi
H
Arakawa
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Masato
M
Okamoto
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Haruo
H
Sugiyama
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Kazuki
K
Sumiyama
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Toshifumi
T
Ohkusa
Shintaro Tsukinaga, Mikio Kajihara, Kazuki Takakura, Zensho Ito, Tomoya Kanai, Keisuke Saito, Shinichiro Takami, Hiroko Kobayashi, Yoshihiro Matsumoto, Shunichi Odahara, Kan Uchiyama, Toshifumi Ohkusa, Shigeo Koido, Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan.
Shigeo
S
Koido
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000097:blood*; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D002478:Cells, Cultured; D017024:Chemotherapy, Adjuvant; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007159:Immunologic Tests; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D015850:Interleukin-6 / Q000097:blood*; D016209:Interleukin-8 / Q000097:blood*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D025721:WT1 Proteins / Q000276:immunology; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; C508606:CXCL8 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D010446:Peptide Fragments; D025721:WT1 Proteins; C583751:WT1 protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine
Chemoimmunotherapy; Delayed-type hypersensitivity; Dendritic cell; Interleukin-6; Interleukin-8; Pancreatic cancer; Wilms’ tumor 1