Abstract 668P
Background
A better characterization of the TIM in advanced SGC might guide immune therapy strategies in these hard-to-treat tumors.
Methods
Patients with advanced and/or metastatic SGC from the multicenter DKTK MASTER program were analyzed. Written informed consent was obtained from all participants. Clinical, histological, RNA-, and whole-exome or whole-genome (WES, WGS) sequencing data were evaluated. Immune activation was defined by combined upregulation of published IFN-y and two inflammation signatures (Ayers et al., Danaher et al.). Immune cellular compositions (RNA-Seq), immune checkpoint expression (RNA-Seq) and tumor mutational burden (TMB, SNV per area of genome from WES or WGS data) were calculated. Results were validated immunohistochemically (IHC; CD3, CD8) using a tissue microarray (TMA) of available samples. Wilcoxon tests were used for statistical analysis, unless otherwise indicated.
Results
90 samples from 88 patients were evaluable (41 female, 47 male, 52 ACC, 36 Non-ACC). An activated TIM was observed in RNA-seq data of 34 samples, including 12 ACC samples, with significant enrichment of inflammation in Non-ACC (Chi-Square p<0.05). Analysis of immune cell compositions revealed activated T-, B- and NK-cells, among others, in transcriptome data from inflamed tumors. IHC in a TMA validated predicted TIM in 12/14 evaluable cases. TMB was significantly higher in Non-ACC (mean 2.8 mut/Mb, range 0.4-13.4) than ACC (mean 0.9 mut/Mb, range 0.3-2.5; p<0.05). TMB was not significantly associated with inflammation. Among evaluated immune checkpoints, TIM-3 and PD1 were most significantly enriched in Non-ACC (p<0.001) and inflamed tumors (p<0.001). VTCN1 was significantly (p<0.001) upregulated in ACC and associated with inflammation-low (p=0.002). TIM was independent from prior treatment with immune checkpoint inhibition (ICI), Multi-TKI, chemotherapy or targeted therapy in ACC and Non-ACC.
Conclusions
In advanced disease, an inflamed TIM was found in 23% of ACC and 61% of Non-ACC with differential expression of immune checkpoints, providing a strong basis for rational immunotherapy trials in these patient subgroups.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Deutsches Konsortium für translationale Krebsforschung (DKTK).
Disclosure
D.T. Rieke: Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb, Lilly; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Role: Alacris Theranostics. F. Klauschen: Financial Interests, Personal, Ownership Interest: Aignostics GmbH; Financial Interests, Personal, Advisory Role: Agilent, AstraZeneca, BMS, Lilly, Merck, Novartis, Roche. I. Tinhofer-Keilholz: Financial Interests, Personal, Advisory Role: Merck KGaA, MerckSerono. P. Horak: Financial Interests, Personal, Advisory Board: Platomics; Financial Interests, Personal, Advisory Role: Roche. U. Keller: Financial Interests, Personal, Advisory Role: Roche, Janssen-Cilag, Takeda, BMS, Gilead, Hexal, Pfizer, AstraZeneca, Pentixafam, Amgen, Novartis; Financial Interests, Personal, Funding: Celgene, MSD. K. Klinghammer: Financial Interests, Personal, Advisory Role: Merck, Sanofi, Roche, Novartis; Financial Interests, Personal, Invited Speaker: MSD, BMS; Financial Interests, Personal, Advisory Board: Glycotope. S. Fröhling: Financial Interests, Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Invited Speaker: Amgen, Eli Lilly, Illuminna, PharmaMar, Roche. S. Ochsenreither: Financial Interests, Personal, Advisory Board: MSD, Merck, BMS, AstraZeneca, Janssen, CureVac, Ipsen; Financial Interests, Personal, Invited Speaker: MSD, Merck, BMS; Financial Interests, Personal, Invited Speaker, Patent of T-cell therapy target: Fred Hutchinson Cancer Research Center. U. Keilholz: Financial Interests, Personal, Other: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Glycotope, Innate, Lilly, MedImmune, MerckSerono, MSD, Novartis, Pfizer, Roche, Sirtex. All other authors have declared no conflicts of interest.