Intratumoral Steroid Production as a Mechanism of Immune Evasion in Adrenocortical Carcinoma (ACC)
Abstract
Adrenocortical carcinoma (ACC) is a rare, aggressive cancer of the adrenal glands. Up to 75 percent of ACC patients will develop metastasis, but available therapies are ineffective and toxic. Immunotherapy has emerged as a promising strategy. The FDA accelerated approval of anti-PD-1 therapy for mismatch repair-deficient tumors including ACC, with rationale that genomically unstable tumors accumulate "neoantigens" that can be unmasked for immune clearance. However, therapy success relies on several factors including tumor immune infiltration, characteristically low in anti-PD-1-resistant tumors. In The Cancer Genome Atlas (TCGA) study on ACC, we observed ACC bears low expression of immune genes and is likely anti-PD-1-resistant. Paradoxically, the most aggressive ACC, with highest mutational burden, are the most immune poor. This ACC subset also exhibits pathologic cortisol excess and high expression of genes involved in steroid production. We hypothesize that in ACC, high concentrations of locally-produced steroids protect cancer cells from the immune system by impairing an anti-tumoral immune response. Aim 1 - Characterization and quantification of ACC intra-tumoral steroidomics and the molecular phenotype of infiltrating immune cells. Aim 2 - Functional characterization of the impact of ACC-secreted steroids on immune cell function and tumor immune infiltrate.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2023
- Accession Number
- AD1221783
Entities
People
- Gary D. Hammer
Organizations
- University of Michigan