AI Article Synopsis

  • Advanced thyroid cancers, particularly anaplastic thyroid cancer (ATC), have limited treatment options and show poor responses to existing therapies like PD1 blockade, highlighting the need for new approaches.
  • Researchers explored combination therapies using ICAM1-targeting CAR T cells and anti-PD1 antibodies, finding that this strategy improved tumor eradication and increased survival in mouse models of ATC.
  • The study suggests that targeting both ICAM1 and PD-L1, which are elevated in advanced thyroid cancers, could provide a promising treatment strategy to manage these aggressive malignancies.

Article Abstract

Purpose: Advanced thyroid cancers, including poorly differentiated and anaplastic thyroid cancer (ATC), are lethal malignancies with limited treatment options. The majority of patients with ATC have responded poorly to programmed death 1 (PD1) blockade in early clinical trials. There is a need to explore new treatment options.

Experimental Design: We examined the expression of PD-L1 (a ligand of PD1) and intercellular adhesion molecule 1 (ICAM1) in thyroid tumors and ATC cell lines, and investigated the PD1 expression level in peripheral T cells of patients with thyroid cancer. Next, we studied the tumor-targeting efficacy and T-cell dynamics of monotherapy and combination treatments of ICAM1-targeting chimeric antigen receptor (CAR) T cells and anti-PD1 antibody in a xenograft model of ATC.

Results: Advanced thyroid cancers were associated with increased expression of both ICAM1 and PD-L1 in tumors, and elevated PD1 expression in CD8 T cells of circulating blood. The expression of ICAM1 and PD-L1 in ATC lines was regulated by the IFNγ-JAK2 signaling pathway. ICAM1-targeted CAR T cells, produced from either healthy donor or patient T cells, in combination with PD1 blockade demonstrated an improved ability to eradicate ICAM1-expressing target tumor cells compared with CAR T treatment alone. PD1 blockade facilitated clearance of PD-L1 high tumor colonies and curtailed excessive CAR T expansion, resulting in rapid tumor clearance and prolonged survival in a mouse model.

Conclusions: Targeting two IFNγ-inducible, tumor-associated antigens-ICAM1 and PD-L1-in a complementary manner might be an effective treatment strategy to control advanced thyroid cancers .

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709864PMC
http://dx.doi.org/10.1158/1078-0432.CCR-20-1523DOI Listing

Publication Analysis

Top Keywords

pd1 blockade
16
advanced thyroid
16
thyroid cancer
12
thyroid cancers
12
pd1 expression
8
car cells
8
expression icam1
8
icam1 pd-l1
8
pd1
7
thyroid
7

Similar Publications

Immune checkpoint inhibitors (ICIs) have been approved for treating various cancers; however, they can cause immune-related adverse events. Generally, ICIs are not associated with an increased risk of infection, however, several reports demonstrated infections caused by nontuberculous mycobacterium (NTM) during ICI therapy. Here, we report a case of NTM shoulder arthritis with acute exacerbation immediately after ICI initiation.

View Article and Find Full Text PDF

First-Line PD-1 Blockade Combined With Chemotherapy for Stage IV Penile Squamous Cell Carcinoma: A Multicenter Retrospective Study.

J Natl Compr Canc Netw

December 2024

1Department of Urology, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: The purpose of this study was to evaluate the efficacy and safety of PD-1 blockade combined with cisplatin and paclitaxel (TP)-based chemotherapy as first-line treatment for advanced penile squamous cell carcinoma (PSCC).

Patients And Methods: A retrospective review was performed of 32 eligible patients with high-risk stage IV (cN3M0-1) PSCC who received first-line PD-1 blockade combined with TP-based chemotherapy at 5 medical centers (2019-2023). Clinical responses were assessed using RECIST version 1.

View Article and Find Full Text PDF

NK cells restrain cytotoxic CD8 T cells in the submandibular gland via PD-1-PD-L1.

Sci Immunol

December 2024

Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA.

The increasing use of anti-programmed cell death 1 (PD-1) immune checkpoint blockade has led to the emergence of immune-related adverse events (irAEs), including dysfunction of the submandibular gland (SMG). In this study, we investigated the immunoregulatory mechanism contributing to the susceptibility of the SMG to irAEs. We found that the SMGs of PD-1-deficient mice and anti-programmed cell death ligand 1 (PD-L1)-treated mice harbor an expanded population of CD8 T cells.

View Article and Find Full Text PDF

Introduction: The NLRP3 inflammasome has been implicated in the initiation of inflammation and tumorigenesis; however, its role in epithelial ovarian cancer (EOC) remains unclear.

Methods: This study employed high-throughput sequencing data, ELISA, clone formation assay, Western blot, and flow cytometric analysis to investigate the specific role of the NLRP3 inflammasome in EOC.

Results: NLRP3 was highly expressed in human EOC tissues and correlated with an unfavorable prognosis.

View Article and Find Full Text PDF

Efficacy of CTLA-4 checkpoint therapy is dependent on IL-21 signaling to mediate cytotoxic reprogramming of PD-1CD8 T cells.

Nat Immunol

December 2024

Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany.

The mechanisms underlying the efficacy of anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) therapy are incompletely understood. Here, by immune profiling responding PD-1CD8 T (T) cell populations from patients with advanced melanoma, we identified differential programming of T cells in response to combination therapy, from an exhausted toward a more cytotoxic effector program. This effect does not occur with anti-PD-1 monotherapy.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!