HLA class I expression and tumor immune infiltration together shape colon cancer immune contexture

Neoplasia, vol. 81, pp. 101357

Abstract

BACKGROUND: The relative contribution of HLA class I molecules-including classical HLA class Ia (HLA-A, -B, -C) and non-classical HLA class Ib (HLA-E, -F, -G)-to shaping the tumor immune microenvironment in colon cancer remains insufficiently defined. We investigated how their expression patterns relate to immune infiltration and clinical outcome. METHODS: In a retrospective cohort of 280 colon cancers, we assessed HLA class Ia and class Ib expression and quantified CD45-positive immune cell infiltration by immunohistochemistry. These features were correlated with clinicopathological variables, microsatellite instability (MSI) status, and previously established genomic immune signatures. RESULTS: High HLA class Ia expression and increased CD45-positive cell infiltration were each associated with improved overall, disease-specific, and progression-free survival. CD45-positive density correlated strongly with Immunologic Constant of Rejection scores. HLA class Ia loss was more frequent in advanced stages and in MSI-H tumors. Among HLA class Ib molecules, only HLA-E expression was associated with favorable disease-specific and progression-free survival. Integrative analysis identified three immune phenotypes with distinct prognostic profiles; tumors characterized by high HLA class Ia expression, low HLA class Ib expression, and high CD45-positive infiltration had the best outcomes. CONCLUSION: Colon cancer immunogenicity is shaped by coordinated patterns of HLA class I expression and immune infiltration. Integrating HLA class Ia/Ib expression with immune cell density provides a refined stratification of tumor immune phenotypes and may support personalized immunotherapeutic decision-making.

Authors 13

1. Hehuan Zhu corresponding Aachen Department of Surgery, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Surgery, Leiden University Medical Center, Leiden, Netherlands. Electronic address: h.zhu@lumc.nl

2. Roos van Nieuwkerk Aachen Department of Surgery, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Surgery, Leiden University Medical Center, Leiden, Netherlands

3. Savannah N. van der Kroft Aachen Department of Surgery, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Surgery, Leiden University Medical Center, Leiden, Netherlands

4. Ronald L. P. van Vlierberghe Aachen Department of Surgery, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Surgery, Leiden University Medical Center, Leiden, Netherlands

5. Marieke E. IJsselsteijn Aachen Department of Pathology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Center, Leiden, Netherlands

6. Weimin Zuo

   Guangdong Medical College

   Affiliation as printed

   Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China

7. Thomas Vauvert F. Hviid

   University of Copenhagen · Zealand University Hospital

   Affiliation as printed

   Department of Clinical Biochemistry, Centre for Immune Regulation and Reproductive Immunology (CIRRI), Zealand University Hospital, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; The ReproHealth Research Consortium, Zealand University Hospital, Copenhagen, Denmark

8. Rob A.�E.�M. Tollenaar Aachen Department of Surgery, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Surgery, Leiden University Medical Center, Leiden, Netherlands

9. Alexander L. Vahrmeijer Aachen Department of Surgery, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Surgery, Leiden University Medical Center, Leiden, Netherlands

10. Davide Bedognetti

    Sidra Medical and Research Center

    Affiliation as printed

    Tumor Biology and Immunology Lab, Research Branch, Sidra Medicine, Doha, Qatar

11. Wouter Hendrickx

    Sidra Medical and Research Center

    Affiliation as printed

    Tumor Biology and Immunology Lab, Research Branch, Sidra Medicine, Doha, Qatar

12. Jessica Roelands corresponding Aachen Department of Pathology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Pathology, Leiden University Medical Center, Leiden, Netherlands. Electronic address: j.p.roelands@lumc.nl

13. Peter J.K. Kuppen corresponding Aachen Department of Surgery, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Surgery, Leiden University Medical Center, Leiden, Netherlands. Electronic address: p.j.k.kuppen@lumc.nl