The TIM3/Gal9 signaling pathway: An emerging target for cancer immunotherapy. Cancer letters Immune checkpoint blockade has shown unprecedented and durable clinical response in a wide range of cancers. T cell immunoglobulin and mucin domain 3 (TIM3) is an inhibitory checkpoint protein that is highly expressed in tumor-infiltrating lymphocytes. In various cancers, the interaction of TIM3 and Galectin 9 (Gal9) suppresses anti-tumor immunity mediated by innate as well as adaptive immune cells. Thus, the blockade of the TIM3/Gal9 interaction is a promising therapeutic approach for cancer therapy. In addition, co-blockade of the TIM3/Gal9 pathway along with the PD-1/PD-L1 pathway increases the therapeutic efficacy by overcoming non-redundant immune resistance induced by each checkpoint. Here, we summarize the physiological roles of the TIM3/Gal9 pathway in adaptive and innate immune systems. We highlight the recent clinical and preclinical studies showing the involvement of the TIM3/Gal9 pathway in various solid and blood cancers. In addition, we discuss the potential of using TIM3 and Gal9 as prognostic and predictive biomarkers in different cancers. An in-depth mechanistic understanding of the blockade of the TIM3/Gal9 signaling pathway in cancer could help in identifying patients who respond to this therapy as well as designing combination therapies. 10.1016/j.canlet.2021.04.011

TIM-3 CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies. Science immunology Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (T), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with expression and motif accessibility. IFN-γ T effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ T. We also observed IFN-γ T within CD19-targeted chimeric antigen receptor T cells, which killed CD19 leukemia cells. An IFN-γ T gene signature was recapitulated in T cells from human cancers, including myeloma and lymphoma. Here, we characterize a T subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional T found in chronic viral infections. Thus, IFN-γ T represent a potential target for immunotherapy of blood cancers. 10.1126/sciimmunol.adg1094