The immunomodulatory molecule TIGIT is expressed by chronic lymphocytic leukemia cells and contributes to anergy

Arruga, Francesca; Rubin, Marta; Papazoglou, Despoina; Iannello, Andrea; Ioannou, Nikolaos; Moia, Riccardo; Rossi, Davide; Gaïdano, Gianluca; Coscia, Marta; Laurenti, Luca; D’Arena, Giovanni; Allan, John N.; Furman, Richard R.; Vaisitti, Tiziana; Ramsay, Alan G.; Deaglio, Silvia

doi:10.3324/haematol.2022.282177

Cited by 6 publications

(4 citation statements)

References 44 publications

(82 reference statements)

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“…First, in patients with chronic lymphocytic leukemia (CLL), AML, or adult acute lymphoblastic leukemia (ALL), TIGIT is commonly upregulated on CD4 + T cells, CD8 + T cells, Foxp3 + γδ T cells, or NK cells compared with healthy individuals [64][65][66][67][68][69][70]. Notably, TIGIT leads to CLL anergy by downregulating B cell receptor signaling [71]. It correlates with T cell exhaustion, NK cell dysfunction, unfavorable responses after chemotherapy, and leukemia relapse after allogeneic hematopoietic stem cell transplantation in AML patients [66,67,69,70].…”

Section: Tigit In Solid Tumors and Hematological Malignanciesmentioning

confidence: 99%

Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

et al. 2023

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Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary cancer treatment modality, offering long-lasting responses and survival benefits for a substantial number of cancer patients. However, the response rates to ICIs vary significantly among individuals and cancer types, with a notable proportion of patients exhibiting resistance or showing no response. Therefore, dual ICI combination therapy has been proposed as a potential strategy to address these challenges. One of the targets is TIGIT, an inhibitory receptor associated with T-cell exhaustion. TIGIT has diverse immunosuppressive effects on the cancer immunity cycle, including the inhibition of natural killer cell effector function, suppression of dendritic cell maturation, promotion of macrophage polarization to the M2 phenotype, and differentiation of T cells to regulatory T cells. Furthermore, TIGIT is linked with PD-1 expression, and it can synergize with PD-1/PD-L1 blockade to enhance tumor rejection. Preclinical studies have demonstrated the potential benefits of co-inhibition of TIGIT and PD-1/PD-L1 in enhancing anti-tumor immunity and improving treatment outcomes in several cancer types. Several clinical trials are underway to evaluate the safety and efficacy of TIGIT and PD-1/PD-L1 co-inhibition in various cancer types, and the results are awaited. This review provides an overview of the mechanisms of TIGIT and PD-1/PD-L1 co-inhibition in anti-tumor treatment, summarizes the latest clinical trials investigating this combination therapy, and discusses its prospects. Overall, co-inhibition of TIGIT and PD-1/PD-L1 represents a promising therapeutic approach for cancer treatment that has the potential to improve the outcomes of cancer patients treated with ICIs.

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Section: Tigit In Solid Tumors and Hematological Malignanciesmentioning

confidence: 99%

Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

et al. 2023

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“… 8 , 13 Peripheral blood analysis of CLL patients showed that TIGIT-positive CD4 T cells were increased over healthy controls, especially in more advanced disease stages. 14 Arruga et al 29 show that TIGIT is more highly expressed on CLL/SLL cells in the peripheral blood when compared with CD19-positive cells from healthy donors. Our results in tissue biopsies of CLL/SLL show frequent TIGIT expression in the TME, but not on lymphoma cells.…”

Section: Discussionmentioning

confidence: 99%

TIGIT is Frequently Expressed in the Tumor Microenvironment of Select Lymphomas

Libert,

Zhao,

Younes

et al. 2023

American Journal of Surgical Pathology

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Immune checkpoint inhibitors against Programmed Cell Death Protein 1/Programmed Cell (PD-1/PD-L1) and CTLA-4/B7 axes have had limited success in hematologic malignancies, requiring the need to explore alternative targets such as T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD155 to improve durable clinical responses. We undertook this study to investigate the expression profile of TIGIT such that the potential efficacy of TIGIT blockade could be mapped among lymphoma subtypes. We validated an immunohistochemical assay for TIGIT and evaluated its expression in lymphoma and tumor microenvironment (TME) cells in 661 lymphoma/leukemia biopsies. Multiplex immunofluorescence was used for correlation with normal TME cell subsets. Tumor or TME TIGIT-positivity was defined as moderate to strong membrane staining in at least 10% of tumor or TME cells, respectively. TME TIGIT expression was correlated with overall survival and progression-free survival and comparison with PD-L1 expression. In most cases, lymphoma cells were TIGIT-negative except for angioimmunoblastic and peripheral T-cell lymphomas, which showed 91% and 47% positivity, respectively. A high proportion of small B-cell lymphoma and anaplastic large cell lymphoma cases had TIGIT-positive TME cells. Chronic lymphocytic leukemia/small lymphocytic lymphoma patients with TIGIT-negative TME cells showed significantly shorter overall survival (P=0.04). No other statistically significant differences were found. When TIGIT was expressed in TME cells, there were a comparable number of TIGIT-positive only and dual TIGIT/PD-L1 positive cases except for more TIGIT-positive only cases in CLL/SLL. TIGIT expression shows distinctive profiles among lymphoma subtypes. Chronic lymphocytic leukemia/small lymphocytic lymphoma and anaplastic large cell lymphoma demonstrated high TME TIGIT expression compared with PD-L1, with a high proportion of dual TIGIT and PD-L1-positivity. Our results are likely to contribute to the design and correlative study of therapeutic response in clinical trials targeting TIGIT alone or in combination with PD1/PDL1.

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“…Interestingly, high TIGIT expression in lymph node biopsies of CLL patients was associated with a lower proliferation rate of CLL cells, whereas CD226 expression was linked to greater proliferation, which is in line with the concept that TIGIT induces anergy of CLL cells. In support of this, Arruga et al show that a high TIGIT to CD226 ratio was predictive for good prognosis in CLL, 1 whereas TIGIT expression was low or absent and CD226 expression was high in Richterâ€™s syndrome, an aggressive transformation of CLL that is driven by highly proliferative B cells. 11 Altogether, this suggests that TIGIT in CLL cells is linked to anergy and a limited proliferation rate ( Figure 1C ).…”

mentioning

confidence: 91%

“…In this issue of Haematologica , Arruga and colleagues add to the list of these genes another interesting molecule which is TIGIT: T-cell immunoreceptor with Ig and ITIM domains. 1 TIGIT is an inhibitory checkpoint receptor that is up-regulated by T cells and natural killer cells upon antigen recognition and limits their response. Like PD-1, it is associated with dysfunctional or exhausted T cells in cancer and is, therefore, currently being tested as a novel immunotherapy target in several clinical trials where dual blockade of PD-(L)1 and TIGIT shows promising early results in cancer patients.…”

mentioning

confidence: 99%