title: Immune Microenvironment in Microsatellite-Instable Endometrial Cancers: Hereditary or Sporadic Origin Matters.
abstract: Purpose:Recent studies show that colorectal tumors with high microsatellite instability (MSI-H) have increased immunogenicity and response to immunotherapy compared with microsatellite-stable (MSS) tumors. It is not yet clear whether MSI-H endometrial cancer may also benefit from these therapies. It is also unknown whether immune response is equivalent in MSI-H endometrial cancer with sporadic or inherited Lynch syndrome origins.Experimental Design:Multiplexed fluorescent IHC was used to compare matched MSI-H (n= 60) and MSS (n= 96) endometrial cancer specimens by evaluating immune cell populations in tumor and stroma compartments. Sporadic MSI-H and Lynch syndrome-associated (LS) MSI-H endometrial cancers were also directly compared.Results:Increased immune cells were present in stroma of MSI-H endometrial cancer compared with MSS, including granzyme B+cells, activated CTLs (CD8+granzyme B+), and PD-L1+cells. Granzyme B+cells and activated CTLs were also increased in the tumor compartment of MSI-H endometrial cancers. Comparing sporadic and LS MSI-H endometrial cancer showed distinct differences in immune cell populations, indicating that mechanisms underlying microsatellite instability alter immune response. Specifically, LS MSI-H endometrial cancer showed increased CD8+cells and activated CTLs in stroma, with reduced macrophages in stroma and tumor compared with sporadic MSI-H. Sporadic MSI-H had increased PD-L1+macrophages in stroma and tumor compared with LS MSI-H endometrial cancer.Conclusions:MSI-H endometrial cancer has increased immune cell infiltration compared with MSS endometrial cancer and the hereditary or sporadic origin of microsatellite instability impacts immune response. Clinical trials to determine the role of immunotherapy in patients with MSI-H endometrial cancer must evaluate Lynch syndrome-related and sporadic MSI-H tumors separately.Clin Cancer Res; 23(15); 4473-81. ©2017 AACR.
authors.affiliation: Department of Gynecologic Oncology, and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Janelle B
authors.initials: JB
authors.lastname: Pakish
authors.affiliation: Department of Gynecologic Oncology, and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Statistics, George R. Brown School of Engineering, Rice University, Houston, Texas.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Han
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Gynecologic Oncology, and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Chisholm
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Gynecologic Oncology, and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Mok
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.affiliation: Department of Gynecologic Oncology, and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
authors.affiliation: Department of Gynecologic Oncology, and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. msyates@mdanderson.org.
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Yates
mesh_terms: D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007167:Immunotherapy; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology