RRC ID 68909
Author Yorita N, Yuge R, Takigawa H, Ono A, Kuwai T, Kuraoka K, Kitadai Y, Tanaka S, Chayama K.
Title Stromal reaction inhibitor and immune-checkpoint inhibitor combination therapy attenuates excluded-type colorectal cancer in a mouse model.
Journal Cancer Lett
Abstract Despite recent advances in cancer immunotherapy, the efficacy of colorectal cancer (CRC) immunotherapy regimens is limited. This study evaluated the combined effect of an anti-PD-1 antibody and a platelet-derived growth factor receptor inhibitor (imatinib) on CRC progression using an orthotopic transplanted mouse model that reproduced the three histological phenotypes of CRC (inflamed-, excluded-, and desert-type). The frequency of each of these phenotypes in 196 human CRC tissue samples was also evaluated. Excluded-type CRC had the highest frequency in human tissue samples. In the mouse model, imatinib suppressed stromal reaction and increased sensitivity to anti-PD-1 treatment in excluded-type CRC. Antitumor effect was observed in mice with excluded-type tumors only after concomitant administration of anti-PD-1 antibody and imatinib. Immunohistological analysis revealed a reduction in stromal volume and an increase in the number of CD8-positive T cells in the tumor nest following combination therapy. RNA sequencing revealed significant activation of immune-related pathways and suppression of stromal-related pathways in transplanted tumors treated with combination therapy compared with tumors treated with anti-PD-1 antibody monotherapy. This combination therapy may prove effective for CRC cases that are unresponsive to anti-PD-1 antibody monotherapy.
Volume 498
Pages 111-120
Published 2021-2-1
DOI 10.1016/j.canlet.2020.10.041
PII S0304-3835(20)30575-9
PMID 33129954
MeSH Aged Animals Antibodies / pharmacology CD8-Positive T-Lymphocytes / drug effects CD8-Positive T-Lymphocytes / metabolism Cell Line, Tumor Colorectal Neoplasms / drug therapy* Colorectal Neoplasms / metabolism Colorectal Neoplasms / therapy* Disease Models, Animal Female Humans Imatinib Mesylate / pharmacology Immune Checkpoint Inhibitors / pharmacology* Immunotherapy / methods Male Mice Mice, Inbred BALB C Programmed Cell Death 1 Receptor / metabolism Protein Kinase Inhibitors / pharmacology* Retrospective Studies
IF 7.36
Human and Animal Cells JLS-V9(RCB2651)