Abstract
AbstractCTLA-4 is an inhibitory immune checkpoint receptor and a negative regulator of anti-tumor T-cell function. This study is aimed for a comparative analysis of CTLA-4+ cells between different tumor entities. To quantify CTLA-4+ cells, 4582 tumor samples from 90 different tumor entities as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. Two different antibody clones (MSVA-152R and CAL49) were validated and quantified using a deep learning framework for automated exclusion of unspecific immunostaining. Comparing both CTLA-4 antibodies revealed a clone dependent unspecific staining pattern in adrenal cortical adenoma (63%) for MSVA-152R and in pheochromocytoma (67%) as well as hepatocellular carcinoma (36%) for CAL49. After automated exclusion of non-specific staining reaction (3.6%), a strong correlation was observed for the densities of CTLA-4+ lymphocytes obtained by both antibodies (r = 0.87; p < 0.0001). A high CTLA-4+ cell density was linked to low pT category (p < 0.0001), absent lymph node metastases (p = 0.0354), and PD-L1 expression in tumor cells or inflammatory cells (p < 0.0001 each). A high CTLA-4/CD3-ratio was linked to absent lymph node metastases (p = 0.0295) and to PD-L1 positivity on immune cells (p = 0.0026). Marked differences exist in the number of CTLA-4+ lymphocytes between tumors. Analyzing two independent antibodies by a deep learning framework can facilitate automated quantification of immunohistochemically analyzed target proteins such as CTLA-4.
Highlights
CTLA-4 is an important inhibitory immune checkpoint receptor
CTLA-4 in normal tissues Using both antibodies, a strong and distinct, predominantly membranous CTLA-4 immunostaining was seen in a subset of T-lymphocytes
For MSVA-152R, an intense granular cytoplasmic staining could be seen in adrenocortical cells and decidua cells while a less
Summary
CTLA-4 (cytotoxic T-lymphocyte-associated protein 4, CD152) is an important inhibitory immune checkpoint receptor. It is expressed on various subtypes of T-lymphocytes including CD4+ and CD8+ T-cells as well as regulatory T-cells[1]. CTLA-4 can compete with its stimulating counterpart CD28 for ligand binding to CD80 and CD862,3. CD28 co-stimulation is required for T-cell activation, whereas CTLA-4 inhibits T-cell response by opposing the actions of CD28-mediated co-stimulation[2,3]. Even though CTLA-4 is expressed on activated CD8+ cytotoxic T-cells, the major physiologic role of CTLA-4 appears to be through downmodulation of non-regulatory T-cell activity and supportively enhancement of regulatory T-cell suppressive activity[1,4,5,6].
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