Abstract LB-253: A comprehensive evaluation of immune checkpoints ligands (ICPLs) in more than 1,000 cancer cell lines (CCLs) identifies specific expression patterns

Abstract

Abstract Background: Targeting ICPs pathways is a promising approach for cancer therapy. Many interactions may exist between ICPLs expressed by antigen-presenting cells (e.g. tumor cells) and receptors on T cells. ICPLs expression in tumor cells can be upregulated by constitutive oncogenic signaling, independently of signals from the microenvironment. Our goal was to identify specific patterns of ICPLs expression across tumor types. Material and methods: Transcript expression levels of IPCLs (PDL1, PDL2, CD80, CD86, B7RP1, B7H3, B7H4, HVEM, CD137L, OX40L, CD70, CD40, and GAL9) and MHC I & II were analyzed in 1,036 human CCLs from the Cancer Cell Line Encyclopedia. An unsupervised hierarchical clustering analysis was performed and the association of KRAS mutation with ICPLs expression was tested. Results: B7H3 was the most widely and highly expressed. A total of 9 clusters with clear patterns were observed (A & B1-8) including 15% (A), 15% (B1), 17% (B2), 3% (B3), 6% (B4), 16% (B5), 9% (B6), 10% (B7) and 9% (B8) of the CCLs. Some malignancies were mostly represented in one cluster (breast, kidney), others in 2 clusters [neuroblastoma, small-cell lung cancer (SCLC)], but the majority were widely distributed among ≥ 3 clusters [non-small cell lung cancer (NSCLC), head&neck (H&N), melanoma, endometrium, colorectal (CRC), sarcomas]. Cluster A included hematological malignancies (HM) (71%) and melanoma (14%) CCLs expressing high levels of MHCII , B7RP1, CD137L, CD70, CD80, CD86, GAL9, HVEM, and/or OX40L. B3 included SCLC (42%) and neuroblastoma (26%) CCLs with low MHCI and ICPLs expression levels. Other clusters were composed of CCLs from various origins. B1 was characterized by high CD137L and CD70 and was mainly represented by kidney (18%), NSCLC (11%), and HM (11%) CCLs. B2 included glioma (15%), NSCLC (14%) and sarcomas (8%) CCLs with high PDL1&2 and OX40L. B4 was enriched in NSCLC (22%) and CRC (18%) lines and was characterized by high expression of MHCII and PDL1 in some CCLs. B5 included NSCLC (18%) and SCLC (15%) among others and was poorly defined in terms of ICPLs expression. B6 included HM (32%), melanoma (16%), endometrium (15%) and gastric (9%) CCLs with high expression of GAL9 and HVEM. B7 included NSCLC (18%), pancreatic (12%), melanoma (10%), glioma (10%) and H&N (5%) CCLs expressing MHCII and high levels of PDL1&2, HVEM, CD137L, CD70 and/or B7H4. B8 included mostly breast (31%), ovarian (13%), H&N (9%) and esophageal (8%) CCLs with high B7-H4 expression levels. KRAS mutation was observed in 143/897 CCLs, mostly in pancreas, NSCLC and CRC CCLs. PDL1 expression was higher in KRAS mutant vs. wild-type NSCLC lines (t-test P=0.0017), while no difference was observed in pancreas and CRC. Conclusion: Patterns of expression of ICPLs ligands are not mainly associated with the tissue of origin. Various ICPLs may be co-expressed by the same tumor cell. The effect of oncogenic drivers on ICPLs expression levels maybe context-dependent. Citation Format: Aurélie Swalduz, Jean-Philippe Foy, Xiaojun Jiang, Roberto Incitti, Sylvie Chabaud, David Pérol, Jean-Yves Blay, Olivier Trédan, Isabelle Treilleux, Aurélien Marabelle, Maurice Pérol, Christophe Caux, Pierre Saintigny. A comprehensive evaluation of immune checkpoints ligands (ICPLs) in more than 1,000 cancer cell lines (CCLs) identifies specific expression patterns. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-253. doi:10.1158/1538-7445.AM2014-LB-253