Abstract LB-350: Robust correlation of Galectin-9 expression with immunological tumor features and outcome in multiple tumor types establishes it as both a novel therapeutic target and a biomarker
Authors: Filipovic Aleksandra , Koide Shohei , Chen Linxiao , Ting David T. , Ilyas Mohammad , Fadhil Wakkas , Rakha Emad , Green Andrew 
Published: September 2020

Galectin-9 (gal-9) is a powerful biological target for cancer immunotherapy and acts as pivotal immuno-suppressor disabling immune-mediated cancer attack and cancer susceptibility to cytotoxic T cell-induced death. We have developed a fully human, anti-gal-9 mAb (LYT-200), aimed for a first in human clinical trial in 2020 in difficult-to-treat cancers. The current study provides compelling evidence of gal-9 significance as a biomarker and a target for therapy.

Tissue sources: &gt;1000 breast (BC) and 500 colorectal cancers (CRC) from Nottingham University and 150 pancreatic ductal adenocarcinoma (PDA) and 100 cholangiocarcinoma (CCA) from the Massachusetts General Hospital. Clinicopathological information were available for correlative analyses. Anti-gal-9 mAb (1G3, Sigma) was used for tissue staining. Independent pathologists assigned intensity score: 0, 1, 2, 3 for gal-9. The following was used: Pearson correlation for two variables; Log-rank test for Kaplan-Meier survival curves; Cox models were fit using the R-function ‘coxph' from the ‘survival' package.

Gal-9 was highly expressed in BC, CRC, PDA, CCA, and in patients' blood compared to healthy controls, indicating its biomarker and therapeutic target potential. High gal-9 in BC correlated with worse 5-year distant metastases free (DMFS; p=0.007) and disease free survival (DFS; p&lt;0.001). High gal-9 retained independent prognostic potential in multivariate analyses with BC stage, grade and size (p=0.006). In PDL-1 positive versus PDL-1 negative tumors, high gal-9 correlated with worse DMFS and DFS (p&lt;0.001). High gal-9 correlated with high tumor grade and mitotic score (p&lt;0.001;p=0.006), triple negative receptor status (p=0.007), and features of an immunosuppressed microenvironment: tumor excluded CD8+ T cells (p=0.02) and intra-tumoral and stromal FOXP3+ cells (p&lt;0.007). Correlative analyses of gal-9 expression with CCR7, CD1a, CD24, CD56, granzyme B, IFNγ, IL17, IL1β, IL23, TGFβ, MHC II, RORγ; and of CRC, PDA and CCA series with comprehensive clinicopathological and molecular tumor characteristics, are under way.

The current study features large, comprehensive cancer patient cohorts providing compelling evidence that gal-9 may be a valuable cancer biomarker and a therapeutic target. BC data collectively confirm the relevance of gal-9 immuno-biology and function in this disease. This study reinforces the importance of considering gal-9 as a theranostic and investigating targeting gal-9 to impede tumor growth through immune rescue in multiple tumor types.

Citation Format: Aleksandra Filipovic, Shohei Koide, Linxiao Chen, David T. Ting, Mohammad Ilyas, Wakkas Fadhil, Emad Rakha, Andrew Green. Robust correlation of Galectin-9 expression with immunological tumor features and outcome in multiple tumor types establishes it as both a novel therapeutic target and a biomarker [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-350.