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

Abstract

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.

The Escape of Cancer from T Cell-Mediated Immune Surveillance: HLA Class I Loss and Tumor Tissue Architecture

“…This tumor classification is in concordance with a progressive immune selection of HLA-I negative tumor variants with successive formation of tumor lesions mainly composed of HLA-I negative cancer cells [17]. In this context, published observations that HLA-I expression in pancreatic and lung cancer inversely correlates with the degree of tumor infiltration with lymphocytes, suggests an active T cell-mediated immune selection in human tumors [18,19]. …”

“…We have recently obtained evidence indicating that tumor tissue architecture changes dramatically with HLA-I loss during cancer progression [13,18]. In lung cancer HLA-I expression strongly correlates with lymphocyte/macrophage infiltration pattern and tumor tissue organization reflecting how an immune-privileged compartment with ineffective anti-tumor immunity is generated during cancer development.…”

“…These changes also affect the pattern of leucocyte infiltration and its localization within or outside the tumor area. We have classified these phases or types of tumor tissue organization as follows: permissive Phase I with HLA-I positive/heterogeneous expression pattern and tumor infiltrating lymphocytes (TILs); and encapsulated/non-permissive Phase II with HLA-I negative tumor cells and peritumoral localization of leucocytes and other immune cells [18]. …”

“…As a result, tumor architecture changes, generating tumor nodes surrounded by different types of T-cells/leucocytes/macrophages and probably other elements of the tumor microenvironment, including Tregs and MDSCs. Furthermore, this phase is also characterized by a marked peritumoral localization of fibroblasts and alternatively activated macrophages providing a physical barrier and forming a “non-permissive” tissue structure (Figure 2b) [18]. Such tumor tissue organization can be observed in a variety of tumors of different histological type [8], however it has not been previously associated with the absence of HLA-I expression in tumors.…”

“…Prevalence of the CD56+ CD16− NK subset with pro-angiogenic activity favoring tumor development and increased expression of inhibitory receptors in tumor infiltrating NK cells was reported in other types of cancer [35,36]. Lung adenocarcinoma cells frequently lose HLA-I expression [18] and theoretically should be heavily infiltrated by NK cells capable of eliminating HLA-I negative tumor cells. However, NK cells are rarely detected in the lung tumor infiltrate.…”