PMID- 38467181
OWN - NLM
STAT- MEDLINE
DCOM- 20240409
LR  - 20240409
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Linking)
VI  - 588
DP  - 2024 Apr 28
TI  - Intratumoral injection of interferon gamma promotes the efficacy of anti-PD1 
      treatment in colorectal cancer.
PG  - 216798
LID - S0304-3835(24)00191-5 [pii]
LID - 10.1016/j.canlet.2024.216798 [doi]
AB  - Immune checkpoint inhibitors (ICIs) offer new options for the treatment of 
      patients with solid cancers worldwide. The majority of colorectal cancers (CRC) 
      are proficient in mismatch-repair (pMMR) genes, harboring fewer tumor antigens 
      and are insensitive to ICIs. These tumors are often found to be immune-deserted. 
      We hypothesized that forcing immune cell infiltration into the tumor 
      microenvironment followed by immune ignition by PD1 blockade may initiate a 
      positive immune cycle that can boost antitumor immunity. Bioinformatics using a 
      public database suggested that IFNgamma was a key indicator of immune status and 
      prognosis in CRC. Intratumoral administration of IFNgamma increased immune cells 
      infiltration into the tumor, but induced PD-L1 expression. A combined treatment 
      strategy using IFNgamma and anti-PD-1 antibody significantly increased T cell killing 
      of tumor cells in vitro and showed synergistic inhibition of tumor growth in a 
      mouse model of CRC. CyTOF found drastic changes in the immune microenvironment 
      upon combined immunotherapy. Treatment with IFNgamma and anti-PD1 antibody in CT26 
      tumors significantly increased infiltration of polymorphonuclear myeloid-derived 
      suppressor cells (PMN-MDSCs). IFNgamma had a more pronounced effect in decreasing 
      intratumoral M2-like macrophages, while PD1 blockade increased the population of 
      CD8+Ly6C + T cells in the tumor microenvironment, creating a more 
      pro-inflammatory microenvironment. Additionally, PD1 induced increased expression 
      of lymphocyte activating 3 (LAG3) in a significant fraction of CD8(+) T cells and 
      Treg cells, indicating potential drug resistance and feedback mechanisms. In 
      conclusion, our work provides preclinical data for the Combined immunotherapy of 
      CRC using intratumoral delivery of IFNgamma and systemic anti-PD1 monoclonoal 
      antibody.
CI  - Copyright (c) 2024 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Tang, Yang
AU  - Tang Y
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China.
FAU - Wei, Jingsun
AU  - Wei J
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China.
FAU - Ge, Xiaoxu
AU  - Ge X
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China.
FAU - Yu, Chengxuan
AU  - Yu C
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China.
FAU - Lu, Wei
AU  - Lu W
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China.
FAU - Qian, Yucheng
AU  - Qian Y
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China.
FAU - Yang, Hang
AU  - Yang H
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China.
FAU - Fu, Dongliang
AU  - Fu D
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China.
FAU - Fang, Yimin
AU  - Fang Y
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China.
FAU - Zhou, Xinyi
AU  - Zhou X
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China.
FAU - Wang, Zhanhuai
AU  - Wang Z
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China.
FAU - Xiao, Qian
AU  - Xiao Q
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China.
FAU - Ding, Kefeng
AU  - Ding K
AD  - Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer 
      Prevention and Intervention, China National Ministry of Education, Key Laboratory 
      of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 
      China; Zhejiang Provincial Clinical Research Center for CANCER, China; Cancer 
      Center of Zhejiang University, Hangzhou, Zhejiang, 310058, China; Center for 
      Medical Research and Innovation in Digestive System Tumors, Ministry of 
      Education, China. Electronic address: dingkefeng@zju.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20240311
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Humans
MH  - *CD8-Positive T-Lymphocytes
MH  - Interferon-gamma/metabolism
MH  - Injections, Intralesional
MH  - Immunotherapy
MH  - *Colorectal Neoplasms/drug therapy/genetics
MH  - Tumor Microenvironment
MH  - Cell Line, Tumor
OTO - NOTNLM
OT  - Colorectal cancer
OT  - Combined immunotherapy
OT  - Interferon gamma
OT  - Programmed cell death protein 1
COIS- Declaration of competing interest The authors declare that they have no conflicts 
      of interest.
EDAT- 2024/03/12 00:42
MHDA- 2024/04/09 06:45
CRDT- 2024/03/11 20:12
PHST- 2023/03/20 00:00 [received]
PHST- 2024/02/21 00:00 [revised]
PHST- 2024/03/05 00:00 [accepted]
PHST- 2024/04/09 06:45 [medline]
PHST- 2024/03/12 00:42 [pubmed]
PHST- 2024/03/11 20:12 [entrez]
AID - S0304-3835(24)00191-5 [pii]
AID - 10.1016/j.canlet.2024.216798 [doi]
PST - ppublish
SO  - Cancer Lett. 2024 Apr 28;588:216798. doi: 10.1016/j.canlet.2024.216798. Epub 2024 
      Mar 11.