In a B16F10 melanoma model, Goldberger and Hauert et al. showed that compared to soluble OVA, membrane-localized OVA was more immunogenic, induced stronger T cell-mediated antitumor responses, and overcame resistance to anti-PD-1. Analysis of patient data showed that a high proportion of membrane-localized neoantigens, particularly at the plasma membrane, correlated with and could help to predict response to ICI and improved overall survival across multiple cancer types, complementary to TMB analyses. The researchers also identified several specific membrane-localized proteins that may serve as biomarkers.
Contributed by Lauren Hitchings
ABSTRACT: Immune checkpoint immunotherapy (ICI) can re-activate immune reactions against neoantigens, leading to remarkable remission in cancer patients. Nevertheless, only a minority of patients are responsive to ICI, and approaches for prediction of responsiveness are needed to improve the success of cancer treatments. While the tumor mutational burden (TMB) correlates positively with responsiveness and survival of patients undergoing ICI, the influence of the subcellular localizations of the neoantigens remains unclear. Here, we demonstrate in both a mouse melanoma model and human clinical datasets of 1,722 ICI-treated patients that a high proportion of membrane-localized neoantigens, particularly at the plasma membrane, correlate with responsiveness to ICI therapy and improved overall survival across multiple cancer types. We further show that combining membrane localization and TMB analyses can enhance the predictability of cancer patient response to ICI. Our results may have important implications for establishing future clinical guidelines to direct the choice of treatment toward ICI.
Author Info: (1) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA; Department of Bioengineering, McGill University, Montreal, QC, Canada. (2) Pritzker School of
Author Info: (1) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA; Department of Bioengineering, McGill University, Montreal, QC, Canada. (2) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (3) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (4) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (5) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (6) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (7) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (8) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (9) Sandia National Laboratories, Livermore, CA, USA. (10) Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA. (11) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA; Ben May Department of Cancer Research, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA; Committee on Cancer Biology, University of Chicago, Chicago, IL, USA. (12) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA; Committee on Cancer Biology, University of Chicago, Chicago, IL, USA. Electronic address: jhubbell@uchicago.edu. (13) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA; Department of General and Visceral Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: priscilla.briquez@uniklinik-freiburg.de.
