The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

Lee, Mi Jin; Woo, Min-Yeong; Heo, Yoo Mi; Kim, Jung-Sik; Kwon, Myung-Hee; Kim, Kyongmin; Park, Sun

doi:10.1016/j.bbrc.2010.09.121

Cited by 15 publications

(19 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study showed that HBV infection could up‐regulate Tim3 expression in NK cells, which may in turn suppress NK cell function in CHB patients . Moreover, inhibition of the Tim3 pathway can enhance the efficacy of tumour vaccines . In accordance with these reports, MIP2 and Tim3 levels in the current study increased with the disease progression of chronic hepatitis B.…”

Section: Discussionsupporting

confidence: 89%

Complementary laboratory indices for predicting the disease status of patients with hepatitis B virus infection

Chen

Zheng

et al. 2013

Journal of Viral Hepatitis

View full text Add to dashboard Cite

To identify complementary laboratory indices for determining the disease status of patients with hepatitis B virus. Subjects were divided into six groups: hepatitis B virus carrier, mild chronic hepatitis B, moderate chronic hepatitis B, severe chronic hepatitis B, fulminant hepatitis B and healthy controls. Serum alanine aminotransferase, total bilirubin and direct bilirubin were measured by an automatic analyser. The levels of T-cell immunoglobulin domain and mucin-domain-containing molecule-3, macrophage inflammatory protein 2, neutrophil gelatinase-associated lipocalin and inducible nitric oxide synthase were measured by ELISA. T-cell immunoglobulin domain, mucin-domain-containing molecule-3, macrophage inflammatory protein 2 and inducible nitric oxide synthase levels were significantly higher in patients with severe chronic hepatitis B compared with those in patients with mild and moderate chronic hepatitis B or fulminant hepatitis B (P < 0.05). When normal or abnormal alanine aminotransferase was present, significant differences between macrophage inflammatory protein 2 and T-cell immunoglobulin domain and mucin-domain-containing molecule-3 levels between patients with mild, moderate, severe chronic hepatitis B or fulminant hepatitis B were observed (P < 0.05). Our results suggest that T-cell immunoglobulin domain and mucin-domain-containing molecule-3 and macrophage inflammatory protein 2 could serve as alanine aminotransferase, direct bilirubin or total bilirubin complementary indices for determining the status of patients with hepatitis B.

show abstract

Section: Discussionsupporting

confidence: 89%

Complementary laboratory indices for predicting the disease status of patients with hepatitis B virus infection

Chen

Zheng

et al. 2013

Journal of Viral Hepatitis

View full text Add to dashboard Cite

show abstract

“…In this regard, interference with TIM-3 signaling is an interesting treatment option, and enhanced tumor vaccine efficacy has been observed by TIM-3 blockade. 92 Interestingly, both TIM-3 and PD-1 were expressed on a subset of exhausted CD8 ϩ T cells in a murine AML model and expression increased during tumor progression. 93 Although either TIM-3 or PD-L1 blockade alone was not sufficient to improve survival, a combination of the 2 antibodies decreased tumor burden and enhanced survival.…”

Section: New Coinhibitory Playersmentioning

confidence: 99%

Coinhibitory molecules in hematologic malignancies: targets for therapeutic intervention

Norde

Hobo

Voort

et al. 2012

Blood

View full text Add to dashboard Cite

The adaptive immune system can be a potent defense mechanism against cancer; however, it is often hampered by immune suppressive mechanisms in the tumor microenvironment. Coinhibitory molecules expressed by tumor cells, immune cells, and stromal cells in the tumor milieu can dominantly attenuate T-cell responses against cancer cells. Today, a variety of coinhibitory molecules, including cytotoxic T lymphocyte-associated antigen-4, programmed death-1, B and T lymphocyte attenuator, LAG3, T-cell immunoglobulin and mucin domain 3, and CD200 receptor, have been implicated in immune escape of cancer cells. Sustained signaling via these coinhibitory molecules results in functional exhaustion of T cells, during which the ability to proliferate, secrete cytokines, and mediate lysis of tumor cells is sequentially lost. In this review, we discuss the influence of coinhibitory pathways in suppressing autologous and allogeneic T cell-mediated immunity against hematologic malignancies. In addition, promising preclinical and clinical data of immunotherapeutic approaches interfering with negative cosignaling, either as monotherapy or in conjunction with vaccination strategies, are reviewed. Numerous studies indicate that coinhibitory signaling hampers the clinical benefit of current immunotherapies. Therefore, manipulation of coinhibitory networks is an attractive adjuvant immunotherapeutic intervention for hematologic cancers after standard treatment with chemotherapy and hematopoietic stem cell transplantation. (Blood. 2012;120(4): 728-736) IntroductionDespite the powerful aspects of immune reactions, most often tumor cells are able to evade immune recognition and destruction. Mechanisms exploited by tumor cells to escape T cell-mediated immunity include disruption of antigen presentation, downregulation of HLA molecules, secretion of immune suppressive cytokines, as well as recruitment of regulatory T cells (T REG ) and myeloid-derived suppressor cells. 1 In the last decade, another powerful immune suppressive mechanism gained much attention: the repressive action of coinhibitory molecules. 2 Activation of T cells is predominantly dependent on both costimulatory and coinhibitory members, including members of the B7/ CD28 family. The balance between positive and negative cosignals determines the functionality of T cells during immunity and tolerance. In addition to the native role of cosignaling, tumor cells can evade immune control by down-regulating costimulatory molecules, such as CD80 and CD86, and up-regulating various coinhibitory ligands, thereby limiting the therapeutic potential of current immunotherapy against cancer.Standard treatment for hematologic cancers includes chemotherapy and radiotherapy, which reduce tumor burden and can induce long-term remission. Moreover, in the past years, new therapeutics, including imatinib, dasatinib, rituximab, bortezomib, and lenalidomide, have been developed that target tumor cells. However, drug resistance and relapse remain major problems. In addition, cellular immunotherapy ...

show abstract

“…We previously reported the tumor-suppressive effect of Tim-3 blockade using Tim-3hIg fusion protein comprising of Tim-3 variable domain (V) and mucin domain linked to the Fc region of human IgG [19].…”

Section: Resultsmentioning

confidence: 99%

“…IgV domain of Tim-3 was ampli ed by PCR using primers (forward primer: 5'-CGG GGT ACC GAT TGG AAA ATG CTT ATG TGT TTG AG and reverse primer: 5'-GAA TTC TGC TTT GAT GTC TAA TTT CAG TTC) and plasmid pIRES2-EGFP-Tim3SVMhIg [19]. The Tim3 V-domain DNA segment was inserted into the pSecTag2C vector (ThermoFisher Scienti c, Waltham, MA, USA) containing mouse immunoglobulin (mIgG2a) CH2CH3 with and without hinge region, and named pSecTag2C-Tim3VdIg and pSecTag2C-Tim3VmIg, respectively.…”

Section: Construction Of Expression Vectors For Tim-3 Blocking Moleculesmentioning

confidence: 99%

“…Furthermore, concomitant blockade of Tim-3 and PD-1 pathways enhances tumor suppression better than blocking either pathway alone [2,[14][15][16]. Several mechanisms are believed to underlie the tumor-suppressive effect of Tim-3 blockade, such as decrease in regulatory T cell frequencies, functional restoration of tumor-in ltrated T cells, increased dendritic cell recruitment to the tumor tissue, and enhanced NK cell activity [7,13,[16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Modulation of the Gut Microbiota Alters the Tumor-Suppressive Efficacy of Tim-3 Pathway Blockade in a Bacterial Species- and Host Factor-Dependent Manner

Lee

Woo

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background T cell immunoglobulin and mucin domain-containing protein-3 (Tim-3) is an immune checkpoint molecule and a potential target for anti-cancer therapy. Alterations in the tumor-suppressive efficacy of immunotherapy due to gut microbiota disturbance have been reported; however, the influence of gut microbiota on the efficacy of Tim-3 blockade is yet to be investigated. In this study, we examined whether gut microbiota manipulation altered the anti-tumor efficacy of Tim-3 blockade. The gut microbiota was manipulated by the administration of antibiotics and oral gavage of bacteria to mice. Results Alterations in the gut microbiome were analyzed by 16S rRNA gene sequencing. Gut dysbiosis triggered by antibiotics attenuated the anti-tumor efficacy of Tim-3 blockade in both C57BL/6 and BALB/c mouse strains. Anti-tumor efficacy was restored via gut microbiota manipulation through oral gavage of fecal bacteria even as antibiotic administration continued. In the case of oral gavage of Enterococcus hirae or Lactobacillus johnsonii, the transferred bacterial species and host mouse strain were critical in determining the anti-tumor efficacy of Tim-3 blockade. Furthermore, oral bacterial gavage did not increase alpha diversity of the gut microbiota in antibiotics-treated mice but did alter microbiome composition, which was associated with restoration of anti-tumor efficacy of Tim-3 blockade. Conclusions Our results highlight the importance of the gut microbiota in anti-cancer immunotherapy responsiveness and indicate that gut microbiota modulation may increase the efficacy of immunotherapy when concomitantly administered with antibiotics. The administered bacterial species and host factors should be considered so as to benefit from gut microbiota modulation.

show abstract

The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

Cited by 15 publications

References 32 publications

Complementary laboratory indices for predicting the disease status of patients with hepatitis B virus infection

Complementary laboratory indices for predicting the disease status of patients with hepatitis B virus infection

Coinhibitory molecules in hematologic malignancies: targets for therapeutic intervention

Modulation of the Gut Microbiota Alters the Tumor-Suppressive Efficacy of Tim-3 Pathway Blockade in a Bacterial Species- and Host Factor-Dependent Manner

Contact Info

Product

Resources

About