Classification of tumor microenvironment immune types based on immune response-associated gene expression

In 2014, the Shizuoka Cancer Center launched project High‑tech Omics‑based Patient Evaluation (HOPE), which features whole exome sequencing (WES) and gene expression profiling (GEP) of fresh surgical specimens from cancer patients. With the development of clinical trials of programmed death‑1 (PD‑1)/PD‑ligand 1 (PD‑L1) blockade, PD‑L1 expression and a high tumor mutation burden become possible biomarkers that could be used to predict immune responses. In this study, based on WES and GEP data from 1,734 tumors from the HOPE project, we established a tumor microenvironment (TME) immune‑type classification consisting of 4 types to evaluate the immunological status of cancer patients and analyze immunological pathways specific for immune types. Project HOPE was conducted in accordance with the Ethical Guidelines for Human Genome and Genetic Analysis Research with the approval of the Institutional Review Board. Based on the expression level of the PD‑L1 and CD8B genes, the immunological status was divided into 4 types as follows: A, PD‑L1+CD8B+; B, PD‑L1+CD8B‑; C, PD‑L1‑CD8B‑; and D, PD‑L1‑CD8B+. Type A, with PD‑L1+ and CD8B+, exhibited an upregulation of cytotoxic T lymphocyte (CTL) killing‑associated genes, T‑cell activation genes, antigen‑presentation and dendritic cell (DC) maturation genes, and T‑cell‑attracting chemokine genes, which promoted Th1 antitumor responses. By contrast, type C, with PD‑L1‑ and CD8B‑, exhibited a low expression of T‑cell‑activating genes and an upregulation of cancer driver gene signaling, which suggested an immune‑suppressive status. With regard to hypermutator tumors, PD‑L1+ hypermutator cases exhibited a specific upregulation of the IL6 gene compared with the PD‑L1‑ cases. On the whole, our data indicate that the classification of the TME immune types may prove to be a useful tool for evaluating the immunological status and predicting antitumor responses and prognosis.