Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma

Abstract

Remarkable efficacy of immune checkpoint inhibition has been reported for several types of solid tumors and early studies in gastric adenocarcinoma are promising. A detailed knowledge about the natural biology of immune checkpoints in gastric adenocarcinoma is essential for clinical and translational evaluation of these drugs. This study is a comprehensive analysis of cytotoxic T lymphocyte associated molecule 4 (CTLA-4) and programmed death 1 ligand 1 (PD-L1) expression in gastric adenocarcinoma. PD-L1 and CTLA-4 were stained on tumor sections of 127 Caucasian patients with gastric adenocarcinoma by immunohistochemistry (IHC) and somatic mutation profiling was performed using targeted nextgeneration sequencing. Expression of PD-L1 and CTLA-4 on lymphocytes in tumor sections, tumordraining lymph nodes (TDLN) and peripheral blood were studied by flow-cytometry and immune-fluorescence microscopy in an additional cohort. PD-L1 and CTLA-4 were expressed in 44.9% (57/ 127) and 86.6% (110/127) of the analyzed gastric adenocarcinoma samples, respectively. Positive tumor cell staining for PD-L1 or CTLA-4 was associated with inferior overall survival. Somatic mutational analysis did not reveal a correlation to expression of PD-L1 or CTLA-4 on tumor cells. Expression of PD-1 (52.2%), PD-L1 (42.2%) and CTLA-4 (1.6%) on tumor infiltrating T cells was significantly elevated compared to peripheral blood. Of note, PD-1 and PD-L1 were expressed far higher by tumor-infiltrating lymphocytes than CTLA-4. In conclusion, specific immune checkpoint-inhibitors should be evaluated in this disease and the combination with molecular targeted therapies might be of benefit. An extensive immune monitoring should accompany these studies to better understand their mode of action in the tumor microenvironment.Abbreviations: CTLA-4, cytotoxic T lymphocyte associated molecule 4; PBMC, peripheral blood mononuclear cells; PD-1, programmed death 1; PD-L1, programmed death 1 ligand 1; TDLN, tumor-draining lymph nodes; UICC, Union International Contre le Cancer.

Computational analysis of morphological and molecular features in gastric cancer tissues

“…ATF7IP/MCAF1 functions for either DNA methylation‐based gene repression or the transcription factor Sp1‐mediated gene activation . On the other hand, PD‐L1 is generally produced by cancer cells to escape immune surveillance, and is a molecular target for cancer immune therapy . Previous report showed that the PD‐L1 gene promoter is regulated by DNA methylation or Sp1 binding in cancer cells .…”

“…36 On the other hand, PD-L1 is generally produced by cancer cells to escape immune surveillance, and is a molecular target for cancer immune therapy. [41][42][43] Previous report showed that the PD-L1gene promoter is regulated by DNA methylation or Sp1 binding in cancer cells. 44,45 There is the possibility that ATF7IP/MCAF1 may control PD-L1 expression via Sp1,as indicated by published ChIP-seq data of colon cancer ( Figure S3A).…”

Chemoradiation-Induced Alteration of Programmed Death-Ligand 1 and CD8+ Tumor-Infiltrating Lymphocytes Identified Patients With Poor Prognosis in Rectal Cancer: A Matched Comparison Analysis

“…The CD8 þ TILs are the main aggressors involved in killing tumor cells, but PD-1/PD-L1 is one of the immune checkpoints underlying immunologic evasion of tumors (1). In regard to functional relationships among the immune checkpoints (35,36), we suggest that more comprehensive analysis with other kinds of immune checkpoints would provide more information. Although PD-L1 expression in tumor-infiltrating immune cells, such as macrophages and lymphocytes, has been evaluated recently, the expression on lymphocytes was not sufficiently observed in our paraffin-embedded tissues.…”

B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies

“…17 To assess the impact of immune escape on tumor associated B cell subsets, we analyzed loss of HLA-I (HLA-ABC) and expression of PD-L1 as two mechanisms of immune evasion described in gastroesophageal adenocarcinoma. 18,19 Altered HLA-expression with either partial or complete loss was detected in 6/27 (22.2%) of primary tumor samples ( Figure 5A, C). Immunohistochemistry showed positive staining for PD-L1 on tumor cells or tumor infiltrating lymphocytes in 16/27 (59.3%) of analyzed samples (Figure 5B, C).…”