Comprehensive transcriptomic analysis of immune checkpoint markers in a pancancer cohort: Implications for response and resistance.

Authors

Hirotaka Miyashita

Hirotaka Miyashita

Mount Sinai Beth Israel, New York, NY

Hirotaka Miyashita , Nicholas J. Bevins , Kartheeswaran Thangathurai , Suzanna Lee , Sarabjot Pabla , Mary Nesline , Sean Glenn , Jeffrey M. Conroy , Paul DePietro , Eitan Rubin , Jason K. Sicklick , Shumei Kato , Razelle Kurzrock

Organizations

Mount Sinai Beth Israel, New York, NY, Department of Pathology, University of California San Diego, La Jolla, CA, The Shraga Segal Dept. for Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer Sheva, Israel, Moores UCSD Cancer Center, La Jolla, CA, OmniSeq, Inc., Buffalo, NY, Ben-Gurion University of the Negev, Beer Sheva, Israel, University of California-San Diego, San Diego, CA, University of California San Diego, Moores Cancer Center, La Jolla, CA, Worldwide Innovative Network for Personalized Cancer Therapy, Paris, France

Research Funding

No funding received

Background: Although immune checkpoint blockade (ICB) has revolutionized cancer treatment, not all patients with cancer benefit from ICB. One possible explanation for poor responders/resistance is the variable expression level of the target molecules (e.g., PD-1 and PD-L1) in the tumor microenvironment. There are recent or ongoing trials targeting variable pathways for immune evasion (e.g., LAG3 or IDO1). It is therefore of interest to know the expression levels related to variable immune checkpoints so that clinical trials can focus on the patients who can benefit from the cognate treatment. Methods: Overall, 514 patients with various solid tumors seen at the University of San Diego, Moores Center for Personalized Cancer Therapy were analyzed. The expression levels of checkpoint markers (ADORA2A, BTLA, CD276, CTLA4, IDO1, IDO2, LAG3, NOS2, PD-1, PD-L1, PD-L2, PVR, TIGIT, TIM3, VISTA, and VTCN) in the tumor samples were measured through RNA sequencing and normalized to internal housekeeping gene profiles, and ranked from 0 to 100 percentile based on a reference population. The expressions of each checkpoint marker were correlated with cancer types, microsatellite instability (MSI), tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) status on immunohistochemistry. Results: In this cohort, 60% were female, median age of 60, and included 30 different tumor types, with colorectal cancer being the most common (27%). The rank values of all checkpoint markers were distributed broadly from 0 to 99 or 100. CD276 and NOS2 had the highest (68th percentile) and lowest (13.5 percentile) median rank values, respectively. When rank values were categorized to “Low” (0-24), “Intermediate” (25-74), and “High” (75-100), 41.6% of patients showed high expression of CD276 while only 13% showed high expression of PD-L1. Each patient had a distinctive protfolio of the categorical expression levels of 16 checkpoint markers. Several checkpoint markers, especially NOS2, showed a significant correlation with cancer type. (median rank values in colorectal, stomach, pancreatic, and breast cancer were 79, 76, 5 and 0 respectively, p < 0.001) Five markers (IDO1, LAG3, PD-1, PD-L1, and TIGIT) showed significant correlation with MSI, while seven markers (CTLA4, IDO1, LAG3, PD-1, PD-L1, PD-L2, and TIGIT) were significantly associated with positive PD-L1 status. However, no significant association was seen based on TMB or tissue-specific grouping of patients. Conclusions: The expression of immune checkpoint markers varies from patient to patient, though transcript expression of several markers correlates with cancer type, MSI, and PD-L1 status. Clinical trials with patient selection based on the expression level of checkpoint markers matched to the corresponding ICB drug are warranted.

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Abstract Details

Meeting

2022 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Developmental Therapeutics—Immunotherapy

Track

Developmental Therapeutics—Immunotherapy

Sub Track

Immunobiology

Citation

J Clin Oncol 40, 2022 (suppl 16; abstr 2555)

DOI

10.1200/JCO.2022.40.16_suppl.2555

Abstract #

2555

Poster Bd #

210

Abstract Disclosures

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