The activity of immune checkpoint inhibitors (ICIs) varies substantially at the extremes of age. We interrogated our tissue database (n = 1,467) to determine if expression of checkpoint molecules or variations in tumor mutational burden (TMB) could explain this phenomenon.
Whole transcriptomic sequencing (RNA-Seq; ∼200x106 reads/tumor) was performed across 1,467 unselected clinical cases (NantHealth; Culver City, CA), with breast, colon, lung and sarcoma reflecting the most common tumor types assessed. To reflect the extremes of age, patients age < 25 and ≥ 80 were compared to the remainder of the cohort. PD-L1 expression was compared across these age-based subsets, along with CTLA4, TIGIT, FOXP3, LAG3, OX40, TIM3 and IDO expression. Putative markers of ICI resistance (e.g, VEGF-A/B/C) were also explored. Tumor mutational burden (TMB; defined as exonic nonsynonymous mutations/megabase [muts/Mb]) was characterized in each subset.
Median age of the cohort was 59 (range, 2-97). Of 1,467 patients, 84 and 65 were age < 25 and ≥ 80, respectively. In patients < 25, significantly lower PD-L1, CTLA4, FOXP3, OX40, LAG3 and TIGIT levels were observed (P < 0.001 for each). No significant differences in IDO, LAG3 or TIM3 were observed in this younger cohort. Older patients had no significant differences in checkpoint molecule expression; curiously, a nonsignificant trend towards increased expression of PD-L1, FOXP3 and LAG3 was observed in the small subset of patients age ≥ 85. No differences in TMB were observed by age. Expression and TMB in each decile of age will be reported.
In pediatric and adolescent and young adult (AYA) patients, lower expression of multiple immune checkpoint molecules may have implications for immune combinatorial strategies. An opposing trend was seen in octagenarians and nonagenarians in our cohort. A detailed further breakdown by histologic subtype will be presented.
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O. Hamid: Consultant: Amgen, Novartis, Roche, BMS, Merck; Speaker: BMS, Genentech, Novartis, Amgen; Contracted research (for institution): AstraZeneca, BMS, Celldex, Genentech, Immunocore, Incyte, Merck, Merck-Serono, MedImmune, Novartis, Pfizer, Rinat, Roche. C. Szeto, S. Reddy: Employee and stockholder: NantOmics LLC. S.K. Pal: Consultant: Pfizer, Inc., Novartis, Aveo Pharmaceuticals, Inc., Myriad Genetics, Genentech, Inc., Exelixis, Bristol-Myers Squibb Company, Astellas Pharma, Inc.; Research/grant support: Medivation, Inc.; Honorarium: Novartis, Medivation, Inc., and Astellas Pharma, Inc. All other authors have declared no conflicts of interest.