Abstract 992P
Background
Immune checkpoint blockade is effective for only a subset of cancers. Targeting T-cell priming markers (TPM) may enhance activity, but clinical trial data suggest that proper application of these agents is a challenge due to immune complexity and heterogeneity. Herein, we interrogated TPM transcriptomics in a pan-cancer cohort.
Methods
Fifteen TPM markers (CD137, CD27, CD28, CD80, CD86, CD40, CD40LG, GITR, ICOS, ICOSLG, OX40, OX40LG, GZMB, IFNG, and TBX21) were analyzed (N=514 patients). Transcript abundance was normalized to internal housekeeping gene profiles and ranked as a percentile (0-100) by comparing RNA levels to a reference population of 753 tumors spanning 35 histologies. Ranks were categorized by range: “Low” (0-24), “Medium” (25-74), and “High” (75-100). TPM’s rank vs histological type, microsatellite instability high (MSI-H), tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) were analyzed (including Bonferroni correction for multiple comparisons).
Results
Among 514 patients (60% female; median age, 61), the most common histological types were colorectal (27%), pancreatic (11%), and breast cancer (10%). Overall, 502 patients (98%) had unique patterns of TPM expression profiles (non-identical to any other patient). No statistically significant association between histological types and TPM expression was seen. In contrast, expression of GZMB and IFNG were significantly higher in tumors with MSI-H, TMB≥10 mutations/mb and PD-L1≥1% by immunohistochemistry (IHC). PD-L1≥1% was also associated with significantly higher expression of CD137, GITR, and ICOS. Patients’ tumors were classified into “Hot”, “Mixed”, or “Cold” clusters (N = 89, 176, and 249, respectively) (Ward’s method). Histological types, MSI status, and TMB were not associated with the clusters, however, the cold cluster showed a significantly lower proportion of tumors with PD-L1 ≥1%. (22% vs 44% in hot and 40% in mixed cluster).
Conclusions
Diverse expression patterns of TPM independent of histological types are described. Individualized selection of patients based on TPM immunomic profiles may be necessary for immunotherapy optimization.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Omniseq.
Disclosure
R. Kurzrock: Financial Interests, Institutional, Sponsor/Funding: Boehringer Ingelheim; Financial Interests, Institutional, Sponsor/Funding: Debiopharm; Financial Interests, Institutional, Sponsor/Funding: Foundation Medicine; Financial Interests, Institutional, Sponsor/Funding: Genentech; Financial Interests, Institutional, Sponsor/Funding: Grifols; Financial Interests, Institutional, Sponsor/Funding: Guardant; Financial Interests, Institutional, Sponsor/Funding: Incyte; Financial Interests, Institutional, Sponsor/Funding: Konica Minolta; Financial Interests, Institutional, Sponsor/Funding: Medimmune; Financial Interests, Institutional, Sponsor/Funding: Merck Serono; Financial Interests, Institutional, Sponsor/Funding: Omniseq; Financial Interests, Institutional, Sponsor/Funding: Pfizer; Financial Interests, Institutional, Sponsor/Funding: Sequenom; Financial Interests, Institutional, Sponsor/Funding: Takeda; Financial Interests, Institutional, Sponsor/Funding: TopAlliance; Financial Interests, Personal, Invited Speaker: Actuate Therapeutics; Financial Interests, Personal, Invited Speaker: Bicara Therapeutics, Inc.; Financial Interests, Personal, Invited Speaker: Biological Dynamics; Financial Interests, Personal, Invited Speaker: Neomed; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: TD2/Volastra; Financial Interests, Personal, Invited Speaker: Turning Point Therapeutics; Financial Interests, Personal, Invited Speaker: X-Biotech; Financial Interests, Personal, Stocks/Shares: CureMatch Inc.; Financial Interests, Personal, Stocks/Shares: IDbyDNA; Financial Interests, Personal, Member of the Board of Directors: CureMatch; Financial Interests, Personal, Member of the Board of Directors: CureMetrix; Financial Interests, Personal, Ownership Interest: CureMatch . N. Bevins: Financial Interests, Personal, Invited Speaker: Thermo Fisher. S. Pabla: Financial Interests, Personal, Stocks/Shares: Omniseq. M. Nesline: Financial Interests, Personal, Stocks/Shares: Omniseq. S. Glenn: Financial Interests, Personal, Stocks/Shares: Omniseq. J. Conroy: Financial Interests, Personal, Stocks/Shares: Omniseq. P. DePietro: Financial Interests, Personal, Stocks/Shares: Omniseq. S. Kato: Financial Interests, Personal, Advisory Board: Foundation Medicine; Financial Interests, Personal, Advisory Board: NeoGenomics; Financial Interests, Personal, Advisory Board: CureMatch; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal and Institutional, Sponsor/Funding: ACT Genomics; Financial Interests, Personal and Institutional, Sponsor/Funding: Sysmex; Financial Interests, Personal and Institutional, Sponsor/Funding: Konica Minolta; Financial Interests, Personal and Institutional, Sponsor/Funding: OmniSeq. All other authors have declared no conflicts of interest.