automated-multiplex-immunofluorescence-panel-for-immuno-oncology

Automated Multiplex Immunofluorescence Panel for Immuno-oncology Studies on Formalin-fixed Carcinoma Tissue Specimens

Continued developments in immuno-oncology require an increased understanding of the mechanisms of cancer immunology. The immunoprofiling analysis of ...

MedImmune

Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment.  and  studies demonstrate that CD38 inhibits CD8 T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment. CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8 T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated. .

CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade.

The role of Runt-related transcription factor 3 ( RUNX3) gene in breast cancer remains not fully understood. We studied the correlation between RUNX3 gene promoter methylation and estrogen receptor (ER) expression status in breast cancer. Three breast cancer cell lines and 113 formalin-fixed, paraffin-embedded breast cancer tissue samples were analyzed for RUNX3 expression. Methylation-specific polymerase chain reaction was used to analyze RUNX3 methylation on the samples. Migration and invasion ability were evaluated in MCF7 cell line (RUNX3 methylated) treated with methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR) to study the effect of RUNX3 methylation status. Our data showed that the expression of RUNX3 was high in MCF10A but not in MCF7 and SKBR3 cell lines, while the RUNX3 promoter showed hypermethylation in MCF7 but not in MCF10A and SKBR3. In tissues samples, Immunohistochemical (IHC) expression of RUNX3 protein was higher in ER-negative samples than in ER-positive cases, and it was negatively correlated with the methylation status of the RUNX3 gene promoter. Proliferation, migration, and invasion of MCF7 were suppressed when 5-Aza-CdR treated. Also, the hypermethylation status of RUNX3 gene promoter was reversed and RUNX3 expression was increased. In summary, our data suggest that hypermethylation of the RUNX3 gene promoter may play an important role in ER-positive breast tumor progression.

RUNX3 Epigenetic Inactivation Is Associated With Estrogen Receptor Positive Breast Cancer.

The development and application of new molecular diagnostic assays based on next-generation sequencing and proteomics require improved methodologies for procurement of target cells from histological sections. Laser microdissection can successfully isolate distinct cells from tissue specimens based on visual selection for many research and clinical applications. However, this can be a daunting task when a large number of cells are required for molecular analysis or when a sizeable number of specimens need to be evaluated.

Article	Year
CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade. Cancer discovery\| PubMed ID: 30012853	2018
RUNX3 Epigenetic Inactivation Is Associated With Estrogen Receptor Positive Breast Cancer. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society\| PubMed ID: 30133331	2018
Computer-Aided Laser Dissection: A Microdissection Workflow Leveraging Image Analysis Tools. Journal of pathology informatics\| PubMed ID: 30622835	2018

Jaime Rodriguez-Canales

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