The absence of HLA class I expression in non‐small cell lung cancer correlates with the tumor tissue structure and the pattern of T cell infiltration

We wanted to analyze whether tumor HLA class I (HLA‐I) expression influences the pattern of the immune cell infiltration and stromal cell reaction in the tumor microenvironment. Tumor tissues obtained from 57 patients diagnosed with lung carcinomas were analyzed for HLA expression and leukocyte infiltration. 28 patients out of the 57 were completely negative for HLA‐I expression (49.1%) or showed a selective HLA‐A locus downregulation (three patients, 5.2%). In 26 out of 57 tumors (47.8%) we detected a positive HLA‐I expression but with a percentage of HLA‐I negative cells between 10 and 25%. The HLA‐I negative phenotype was produced by a combination of HLA haplotype loss and a transcriptional downregulation of β2‐microglobulin (β2‐m) and LMP2 and LMP7 antigen presentation machinery genes. The analysis and localization of different immune cell populations revealed the presence of two major and reproducible patterns. One pattern, which we designated “immune‐permissive tumor microenvironment (TME),” was characterized by positive tumor HLA‐I expression, intratumoral infiltration with cytotoxic T‐CD8+ cells, M1‐inflammatory type macrophages, and a diffuse pattern of FAP+ cancer‐associated fibroblasts. In contrast, another pattern defined as “non‐immune‐permissive TME” was found in HLA‐I negative tumors with strong stromal‐matrix interaction, T‐CD8+ cells surrounding tumor nests, a dense layer of FAP+ fibroblasts and M2/repair‐type macrophages. In conclusion, this study revealed marked differences between HLA class I‐positive and negative tumors related to tissue structure, the composition of leukocyte infiltration and stromal response in the tumor microenvironment. What's new? Immune cell infiltration in tumors has great clinical significance, but the factors pre‐determining different infiltration patterns remain unclear. Many tumors are however known to evade T lymphocyte responses by down‐regulating HLA‐I expression. Here, the authors demonstrate, in lung cancer, that tumor tissue structure strongly correlates with HLA‐I expression and identify two patterns of leukocyte infiltration. HLA‐I‐positive tumors are heavily infiltrated by CD8+ T lymphocytes and M1 macrophages mixed with stromal cells in an immune‐permissive tumor microenvironment (TME). In contrast, HLA‐I‐negative tumor nodules are encapsulated by a stroma with CD8+ T lymphocytes, M2 macrophages and FAP+ fibroblasts in a non‐immune‐permissive TME.