High CTLA-4 transcriptomic expression correlates with high expression of other checkpoints and with immunotherapy outcome.

Background

CTLA-4 impedes the immune system's antitumor response. There are two Food and Drug Administration-approved anti-CTLA-4 agents - ipilimumab and tremelimumab - both used together with anti-PD-1/PD-L1 agents.

Objective

To assess the prognostic implications and immunologic correlates of high CTLA-4 in tumors of patients on immunotherapy and those on non-immunotherapy treatments.

Design/methods

We evaluated RNA expression levels in a clinical-grade laboratory and clinical correlates of CTLA-4 and other immune checkpoints in 514 tumors, including 489 patients with advanced/metastatic cancers and full outcome annotation. A reference population (735 tumors; 35 histologies) was used to normalize and rank transcript abundance (0-100 percentile) to internal housekeeping gene profiles.

Results

The most common tumor types were colorectal (140/514, 27%), pancreatic (55/514, 11%), breast (49/514, 10%), and ovarian cancers (43/514, 8%). Overall, 87 of 514 tumors (16.9%) had high CTLA-4 transcript expression (⩾75th percentile rank). Cancers with the largest proportion of high CTLA-4 transcripts were cervical cancer (80% of patients), small intestine cancer (33.3%), and melanoma (33.3%). High CTLA-4 RNA independently/significantly correlated with high PD-1, PD- L2, and LAG3 RNA levels (and with high PD-L1 in univariate analysis). High CTLA-4 RNA expression was not correlated with survival from the time of metastatic disease [

Conclusion

High CTLA-4, especially when combined with high PD-L1 transcript expression, was a significant positive predictive biomarker for better outcomes (PFS and OS) in patients on immunotherapy.

High CTLA-4 expression and immunotherapy outcome High CTLA-4 expression was not a prognostic factor for survival in patients not receiving ICIs but was a significant positive predictive biomarker for better outcome (PFS and OS) in patients on immunotherapy, perhaps because it correlated with expression of other checkpoints such as PD-1 and PD-L2.

Informations de copyright

© The Author(s), 2024.

Déclaration de conflit d'intérêts

RK has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, OmniSeq, Pfizer, Sequenom, Takeda, and TopAlliance and from the NCI; as well as consultant and/or speaker fees and/or advisory board/consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Datar Cancer Genetics, Daiichi, EISAI, EOM Pharmaceuticals, Iylon, LabCorp, Merck, NeoGenomics, Neomed, Pfizer, Prosperdtx, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech; has an equity interest in CureMatch Inc. and IDbyDNA; serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch. SK serves as a consultant for Medpace, Foundation Medicine, NeoGenomics, and CureMatch. He receives speaker’s fee from Chugai, Roche/Genentech and Bayer, and advisory board for Pfizer. He has research funding from ACT Genomics, Sysmex, Konica Minolta, OmniSeq, Personalis, and Function Oncology. MN, SP, JC, and PD are employees of OmniSeq. NK, SL, and DN have no disclosures.