TY - JOUR
T1 - Changes in the Tumor Immune Microenvironment during Disease Progression in Patients with Ovarian Cancer
AU - Westergaard, Marie Christine Wulff
AU - Milne, Katy
AU - Pedersen, Magnus
AU - Hasselager, Thomas
AU - Olsen, Lars Rønn
AU - Anglesio, Michael S.
AU - Borch, Troels Holz
AU - Kennedy, Mia
AU - Briggs, Gillian
AU - Ledoux, Stacey
AU - Kreuzinger, Caroline
AU - von der Decken, Isabel
AU - Donia, Marco
AU - Castillo-Tong, Dan Cacsire
AU - Nelson, Brad H.
AU - Svane, Inge Marie
N1 - Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/12/18
Y1 - 2020/12/18
N2 - Anti-PD1/PDL1 therapy has proven efficacious against many cancers but only reached modest objective response rates against recurrent ovarian cancer. A deeper understanding of the tumor microenvironment (TME) may reveal other immunosuppressive mechanisms that warrant investigation as immunotherapeutic targets for this challenging disease. Matched primary and recurrent tumors from patients with high-grade serous ovarian carcinoma (HGSC) were analyzed by multicolor immunohistochemistry/immunofluorescence for the presence of T cells, B cells, macrophages, and for the expression of immunosuppressive and HLA molecules. Cancer- and immune-related gene expression was assessed by NanoString analysis. Recurrent tumors showed increased infiltration by immune cells, displayed higher expression of PDL1, IDO, and HLA molecules, and contained more stromal tissue. NanoString analysis demonstrated increased expression of gene signatures related to chemokines and T cell functions in recurrent tumors. The ovarian tumors showed high gene expression of LAG3 and HAVCR2 (TIM3) and enhanced levels of TIGIT and CTLA4 in recurrent tumors compared to primary tumors. The majority of HGSC developed into a more inflamed phenotype during progression from primary to recurrent disease, including indications of adaptive immune resistance. This suggests that recurrent tumors may be particularly sensitive to inhibition of adaptive immune resistance mechanisms.
AB - Anti-PD1/PDL1 therapy has proven efficacious against many cancers but only reached modest objective response rates against recurrent ovarian cancer. A deeper understanding of the tumor microenvironment (TME) may reveal other immunosuppressive mechanisms that warrant investigation as immunotherapeutic targets for this challenging disease. Matched primary and recurrent tumors from patients with high-grade serous ovarian carcinoma (HGSC) were analyzed by multicolor immunohistochemistry/immunofluorescence for the presence of T cells, B cells, macrophages, and for the expression of immunosuppressive and HLA molecules. Cancer- and immune-related gene expression was assessed by NanoString analysis. Recurrent tumors showed increased infiltration by immune cells, displayed higher expression of PDL1, IDO, and HLA molecules, and contained more stromal tissue. NanoString analysis demonstrated increased expression of gene signatures related to chemokines and T cell functions in recurrent tumors. The ovarian tumors showed high gene expression of LAG3 and HAVCR2 (TIM3) and enhanced levels of TIGIT and CTLA4 in recurrent tumors compared to primary tumors. The majority of HGSC developed into a more inflamed phenotype during progression from primary to recurrent disease, including indications of adaptive immune resistance. This suggests that recurrent tumors may be particularly sensitive to inhibition of adaptive immune resistance mechanisms.
KW - Adaptive immune resistance
KW - Immune checkpoints
KW - Multicolor immunohistochemistry (IHC)
KW - NanoString
KW - Ovarian cancer
KW - TILs
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85098246046&partnerID=8YFLogxK
U2 - 10.3390/cancers12123828
DO - 10.3390/cancers12123828
M3 - Journal article
C2 - 33352957
SN - 2072-6694
VL - 12
SP - 1
EP - 19
JO - Cancers
JF - Cancers
IS - 12
M1 - 3828
ER -