Abstract
We generated a comprehensive atlas of the immunologic cellular networks within human malignant pleural mesothelioma (MPM) using mass cytometry. Data-driven analyses of these high-resolution single-cell data identified 2 distinct immunologic subtypes of MPM with vastly different cellular composition, activation states, and immunologic function; mass spectrometry demonstrated differential abundance of MHC-I and -II neopeptides directly identified between these subtypes. The clinical relevance of this immunologic subtyping was investigated with a discriminatory molecular signature derived through comparison of the proteomes and transcriptomes of these 2 immunologic MPM subtypes. This molecular signature, representative of a favorable intratumoral cell network, was independently associated with improved survival in MPM and predicted response to immune checkpoint inhibitors in patients with MPM and melanoma. These data additionally suggest a potentially novel mechanism of response to checkpoint blockade: requirement for high measured abundance of neopeptides in the presence of high expression of MHC proteins specific for these neopeptides.
Keywords:
Cancer immunotherapy; Expression profiling; Immunology; Oncology; Proteomics.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Antigens, Neoplasm / genetics
-
Antigens, Neoplasm / immunology*
-
Antineoplastic Agents, Immunological / pharmacology
-
Antineoplastic Agents, Immunological / therapeutic use
-
Cell Line, Tumor
-
Costimulatory and Inhibitory T-Cell Receptors / antagonists & inhibitors
-
Costimulatory and Inhibitory T-Cell Receptors / immunology
-
Gene Expression Regulation, Neoplastic / genetics
-
Gene Expression Regulation, Neoplastic / immunology*
-
Humans
-
Kaplan-Meier Estimate
-
Lung / pathology
-
Lung / surgery
-
Lung Neoplasms / genetics
-
Lung Neoplasms / immunology*
-
Lung Neoplasms / mortality
-
Lung Neoplasms / therapy
-
Mass Spectrometry / methods
-
Mesothelioma / genetics
-
Mesothelioma / immunology*
-
Mesothelioma / mortality
-
Mesothelioma / therapy
-
Mesothelioma, Malignant
-
Pleura / pathology
-
Pleura / surgery
-
Pleural Neoplasms / genetics
-
Pleural Neoplasms / immunology*
-
Pleural Neoplasms / mortality
-
Pleural Neoplasms / therapy
-
Prognosis
-
Prospective Studies
-
Proteogenomics / methods
-
Retrospective Studies
-
Single-Cell Analysis / methods
-
Transcriptome / genetics
-
Transcriptome / immunology*
-
Treatment Outcome
-
Tumor Microenvironment / genetics
-
Tumor Microenvironment / immunology
Substances
-
Antigens, Neoplasm
-
Antineoplastic Agents, Immunological
-
Costimulatory and Inhibitory T-Cell Receptors