PMID- 32497200
OWN - NLM
STAT- MEDLINE
DCOM- 20210618
LR  - 20210618
IS  - 1460-2105 (Electronic)
IS  - 0027-8874 (Print)
IS  - 0027-8874 (Linking)
VI  - 113
IP  - 2
DP  - 2021 Feb 1
TI  - Tumor Microenvironment Immune Response in Pancreatic Ductal Adenocarcinoma 
      Patients Treated With Neoadjuvant Therapy.
PG  - 182-191
LID - 10.1093/jnci/djaa073 [doi]
AB  - BACKGROUND: Neoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin 
      (FOLFIRINOX) and chemoradiation have been used to downstage borderline and 
      locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant 
      therapy-induced tumor immune response contributes to the improved survival is 
      unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune 
      response towards PDAC. METHODS: Clinicopathological variables were collected for 
      surgically resected PDACs at the Massachusetts General Hospital (1998-2016). 
      Neoadjuvant regimens included FOLFIRINOX with or without chemoradiation, proton 
      chemoradiation (25 Gy), photon chemoradiation (50.4 Gy), or no neoadjuvant 
      therapy. Human leukocyte antigen (HLA) class I and II expression and immune cell 
      infiltration (CD4+, FoxP3+, CD8+, granzyme B+ cells, and M2 macrophages) were 
      analyzed immunohistochemically and correlated with clinicopathologic variables. 
      The antitumor immune response was compared among neoadjuvant therapy regimens. 
      All statistical tests were 2-sided. RESULTS: Two hundred forty-eight PDAC 
      patients were included. The median age was 64 years and 50.0% were female. HLA-A 
      defects were less frequent in the FOLFIRINOX cohort (P = .006). HLA class II 
      expression was lowest in photon and highest in proton patients (P = .02). The 
      FOLFIRINOX cohort exhibited the densest CD8+ cell infiltration (P < .001). 
      FOLFIRINOX and proton patients had the highest CD4+ and lowest T regulatory 
      (FoxP3+) cell density, respectively. M2 macrophage density was statistically 
      significantly higher in the treatment-naive group (P < .001) in which dense M2 
      macrophage infiltration was an independent predictor of poor overall survival. 
      CONCLUSIONS: Neoadjuvant FOLFIRINOX with or without chemoradiation may induce 
      immunologically relevant changes in the tumor microenvironment. It may reduce 
      HLA-A defects, increase CD8+ cell density, and decrease T regulatory cell and M2 
      macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from 
      combinations with checkpoint inhibitors, which can enhance patients' antitumor 
      immune response.
CI  - (c) The Author(s) 2020. Published by Oxford University Press. All rights reserved. 
      For permissions, please email: journals.permissions@oup.com.
FAU - Michelakos, Theodoros
AU  - Michelakos T
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Cai, Lei
AU  - Cai L
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
AD  - Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical 
      University, Chongqing, China.
FAU - Villani, Vincenzo
AU  - Villani V
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Sabbatino, Francesco
AU  - Sabbatino F
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Kontos, Filippos
AU  - Kontos F
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Fernandez-Del Castillo, Carlos
AU  - Fernandez-Del Castillo C
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Yamada, Teppei
AU  - Yamada T
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Neyaz, Azfar
AU  - Neyaz A
AD  - Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Taylor, Martin S
AU  - Taylor MS
AD  - Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Deshpande, Vikram
AU  - Deshpande V
AD  - Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Kurokawa, Tomohiro
AU  - Kurokawa T
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Ting, David T
AU  - Ting DT
AD  - Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      Harvard Medical School, Boston, MA, USA.
FAU - Qadan, Motaz
AU  - Qadan M
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Weekes, Colin D
AU  - Weekes CD
AD  - Department of Hematology/Oncology, Massachusetts General Hospital, Harvard 
      Medical School, Boston, MA, USA.
FAU - Allen, Jill N
AU  - Allen JN
AD  - Department of Hematology/Oncology, Massachusetts General Hospital, Harvard 
      Medical School, Boston, MA, USA.
FAU - Clark, Jeffrey W
AU  - Clark JW
AD  - Department of Hematology/Oncology, Massachusetts General Hospital, Harvard 
      Medical School, Boston, MA, USA.
FAU - Hong, Theodore S
AU  - Hong TS
AD  - Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical 
      School, Boston, MA, USA.
FAU - Ryan, David P
AU  - Ryan DP
AD  - Department of Hematology/Oncology, Massachusetts General Hospital, Harvard 
      Medical School, Boston, MA, USA.
FAU - Wo, Jennifer Y
AU  - Wo JY
AD  - Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical 
      School, Boston, MA, USA.
FAU - Warshaw, Andrew L
AU  - Warshaw AL
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Lillemoe, Keith D
AU  - Lillemoe KD
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Ferrone, Soldano
AU  - Ferrone S
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
FAU - Ferrone, Cristina R
AU  - Ferrone CR
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston, MA, USA.
LA  - eng
GR  - R03 CA231766/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Natl Cancer Inst
JT  - Journal of the National Cancer Institute
JID - 7503089
RN  - 0 (folfirinox)
RN  - 04ZR38536J (Oxaliplatin)
RN  - 7673326042 (Irinotecan)
RN  - Q573I9DVLP (Leucovorin)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Adenocarcinoma/*drug therapy/pathology
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage
MH  - Carcinoma, Pancreatic Ductal/*drug therapy/genetics/immunology/pathology
MH  - Chemoradiotherapy/adverse effects
MH  - Female
MH  - Fluorouracil/administration & dosage
MH  - Genes, MHC Class I/genetics
MH  - Humans
MH  - Immunity/drug effects/genetics
MH  - Irinotecan/administration & dosage
MH  - Leucovorin/administration & dosage
MH  - Male
MH  - Middle Aged
MH  - Neoadjuvant Therapy/adverse effects
MH  - Oxaliplatin/administration & dosage
MH  - Tumor Microenvironment/*drug effects/immunology
PMC - PMC7850539
EDAT- 2020/06/05 06:00
MHDA- 2021/06/22 06:00
PMCR- 2021/06/04
CRDT- 2020/06/05 06:00
PHST- 2020/01/23 00:00 [received]
PHST- 2020/04/08 00:00 [revised]
PHST- 2020/05/11 00:00 [accepted]
PHST- 2020/06/05 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/06/05 06:00 [entrez]
PHST- 2021/06/04 00:00 [pmc-release]
AID - 5851438 [pii]
AID - djaa073 [pii]
AID - 10.1093/jnci/djaa073 [doi]
PST - ppublish
SO  - J Natl Cancer Inst. 2021 Feb 1;113(2):182-191. doi: 10.1093/jnci/djaa073.