1246 Immune related adverse events to checkpoint inhibitors are associated with altered regulatory T cell phenotypes and resemble CTLA4-deficient patients
Year: 2023
Type: conference-abstract
Abstract: Background Combination immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death protein 1 (PD-1) have induced durable responses in many malignancies but produce high grade immune related adverse events (irAEs) in up to half of patients. Given this high rate of toxicity, there is a growing interest in defining cell types responsible for irAE development and biomarkers to predict who is at risk. Methods To address this unmet need, we used mass cytometry with 33 markers in a longitudinal manner to assess cellular phenotypic differences in PBMCs among patients who either do or do not develop irAEs in patients with melanoma and renal cell carcinoma. We then compared these findings using mass cytometry on patients with known genetic CTLA-4 Haploinsufficiency, an inborn error of immunity that results in decreased CTLA-4 expression that we hypothesized may phenocopy CTLA-4 blockade. Results A cohort of patients with metastatic melanoma (n=14) were retrospectively classified as grade 2+ irAE+ (n=8) or irAE- (n=6) based on CTCAE 5.0 criteria. PBMCs were obtained prior to combination anti-CTLA-4/anti-PD-1 and 3 weeks after treatment initiation. Initial clustering using t-distributed stochastic neighbor embedding revealed temporal increases in double negative T cell frequencies in irAE+ patients but not irAE- patients. Subpopulation analysis of the CD4+ Cluster revealed changes in naïve-like and regulatory T cell (Treg)-like frequencies from both irAE- and irAE+ groups and were confirmed via manual gating. However, the irAE+ group had significant decreases in the frequency and MFI of CCR6+ Tregs and significant increases in the frequency and MFI of CD38+ Tregs which were not observed in the irAE- group. These findings were confirmed in an independent cohort of patients with renal cell carcinoma (RCC, n irAE-= 4, n grade 2+ irAE+=9). We then compared patient samples from patients with CTLA-4 haploinsufficiency (n=7) and healthy controls (n=17) and found patients with CTLA-4 haploinsufficiency also had significant reductions in CCR6+ Tregs and increases in CD38+ Tregs compared to healthy controls. Conclusions Our study demonstrates that early changes in CCR6+ Treg and CD38+ Treg frequencies within the first 3 weeks of combination therapy could serve as a potential predictive biomarker for adverse event development and these cellular phenotypes may contribute to disease pathogenesis. Furthermore, our data with CTLA-4 deficiency suggests that CTLA-4 loss is responsible for these regulatory T cell changes. Targeting these specific Treg subsets may be valuable in limiting severe toxicity. Ethics Approval This study obtained ethics approval by the Vanderbilt University Medical Center Institutional Review Board (#191213 and #160979). Participants gave informed consent prior to sample collection.
Institution: Vanderbilt University Medical Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4388068608