Spatial Cancer-Immune Phenotypes Predict Shorter Recurrence-Free Survival in the No Specific Molecular Profile Molecular Subtype of Endometrial Carcinoma

Dario de Biase; Jacopo Lenzi; Claudio Ceccarelli; Thais Maloberti; Marco Grillini; Camelia Alexandra Coadǎ; Claudio Zamagni; Pierandrea De Iaco; Anna Myriam Perrone; Donatella Santini; Martin Köbel; Cheng-Han Lee; Giovanni Tallini; Antonio De Leo

doi:10.1016/j.modpat.2024.100624

Spatial Cancer-Immune Phenotypes Predict Shorter Recurrence-Free Survival in the No Specific Molecular Profile Molecular Subtype of Endometrial Carcinoma

Mod Pathol. 2024 Sep 24;38(1):100624. doi: 10.1016/j.modpat.2024.100624. Online ahead of print.

Authors

Affiliations

¹ Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Pharmacy and Biotechnology (FaBit), University of Bologna, Bologna, Italy.
² Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
³ Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
⁴ Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
⁵ Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
⁶ Department of Morpho-functional Sciences, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania.
⁷ IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
⁸ Division of Gynecologic Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
⁹ Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
¹⁰ Department of Pathology and Laboratory Medicine, University of Alberta, Edmonton, AB, Canada.
¹¹ Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
¹² Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy. Electronic address: antonio.deleo@unibo.it.

PMID: 39326496
DOI: 10.1016/j.modpat.2024.100624

Abstract

Compartmentation of the immune response into 3 main spatial cancer-immune phenotypes (SCIs) - inflamed, excluded, and desert - has been proposed as the main predictor of response to immune checkpoint inhibitors in solid tumors. The objective of the study was to define and characterize the SCI in a consecutive series of 213 endometrial carcinomas (ECs) by correlating it with molecular subtypes, clinicopathologic features, and prognosis. Immunohistochemistry (IHC) and next-generation sequencing were used to assign surrogate molecular EC subtypes: POLE mutant (POLE), mismatch repair deficient (MMRd), TP53 mutant (p53abn), and no specific molecular profile (NSMP). Immune cell markers (CD20, CD3, CD8, CD68, PD-L1) were assessed by IHC on whole sections and quantified by digital image analysis to define the 3 SCIs. ECs were stratified into 4 molecular subtypes: 17 (8.0%) POLE, 68 (31.9%) MMRd, 42 (19.7%) p53abn, and 86 (40.4%) NSMP. SCI determination showed 105 (49.3%) inflamed, 62 (29.1%) desert, and 46 (25.6%) excluded tumors. The inflamed phenotype was more prevalent in MMRd (64.7%) and POLE (76.5%) subtypes compared with NSMP (45.3%) and p53abn (21.4%). SCI revealed a strong correlation with disease-free survival in NSMP tumors: inflamed 96.2%, desert 83.2%, and excluded 40.5%. The SCI prognostic impact was also maintained in NSMP cases treated with adjuvant therapy resulting in a significant difference in recurrence between the inflamed and excluded phenotypes. To simplify SCI determination, a subset of immune cell markers was selected as appropriate to define the 3 SCI patterns: high intraepithelial CD8 for the inflamed phenotype; CD68, CD20, and PD-L1 to discriminate between desert and excluded tumors. The integration of SCI into molecular classification could be a promising opportunity to improve the prognostic risk stratification of patients and may guide the therapeutic approach, particularly in the NSMP subtype. Thus, the different patterns of immune response are a new prognostic parameter in the NSMP subtype.

Keywords: endometrial carcinoma; immune response; molecular classification; prognosis; spatial-cancer immune phenotype; tumor microenvironment.