scholarly journals Induction of Therapeutic Protection in an HPV16-Associated Mouse Tumor Model Through Targeting the Human Papillomavirus-16 E5 Protein to Dendritic Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Oscar Badillo-Godinez ◽  
Adolfo Pedroza-Saavedra ◽  
Veronica Valverde-Garduño ◽  
Victor Bermudez-Morales ◽  
Minerva Maldonado-Gama ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Specific Antigen ◽  
Tumor Model ◽  
Immune Checkpoint Blockade ◽  
Premalignant Lesions ◽  
Mouse Tumor ◽  
Human Papillomavirus 16

HPV E5 is an oncoprotein mainly expressed in premalignant lesions, which makes it an important target for a vaccine to prevent or cure cervical cancer (CC). In this study, we evaluated whether E5 targeted to DEC-205, present in dendritic cells (DCs), could induce a therapeutic protection against HPV16-induced tumor cells in a mouse model. The HPV-16 E5 (16E5) protein was cross-linked to a monoclonal antibody (mAb) specific to mouse DEC-205 (anti-DEC-205:16E5) or to an isotype control mAb (isotype:16E5). Rotavirus VP6 was cross-linked to the mouse anti-DEC-205 mAb (anti-DEC-205:VP6) as a non-specific antigen control. BALB/c mice were inoculated subcutaneously (s.c.) with the 16E5-expressing BMK-16/myc tumor cells, and 7 and 14 days later the mice were immunized s.c. with the conjugates, free 16E5 or PBS in the presence of adjuvant. Tumor growth was monitored to evaluate protection. A strong protective immune response against the tumor cells was induced when the mice were inoculated with the anti-DEC-205:16E5 conjugate, since 70% of the mice controlled the tumor growth and survived, whereas the remaining 30% developed tumors and died by day 72. In contrast, 100% of the mice in the control groups died by day 30. The anti-DEC-205:16E5 conjugate was found to induce 16E5-specific memory T cells, with a Th1/Th17 profile. Both CD4+ and CD8+ T cells contributed to the observed protection. Finally, treating mice that had developed tumors with an anti-PD-1 mAb, delayed the tumor growth for more than 20 days. These results show that targeting 16E5 to DEC-205, alone or combined with an immune checkpoint blockade, could be a promising protocol for the treatment of the early stages of HPV-associated cancer.

508 Different neoantigen expression patterns impact the strength of anti-tumor immune responses

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A544-A544
Author(s):  
Kim Nguyen ◽  
Stefani Spranger ◽  
Christopher Copeland
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Expression Patterns ◽  
Tumor Model ◽  
Immune Checkpoint Blockade ◽  
List Type ◽  
Patient Response

BackgroundMany cancer immunotherapies depend on the ability of cytotoxic CD8+ T cells to recognize neoantigens on MHCI complexes to effectively eliminate tumor cells. However, patient response following immunotherapy is highly variable, with recent work suggesting that neoantigen expression patterns can impair patient response. Specifically, it was observed that the immune response is dampened when neoantigens are expressed only by a subset of tumor cells (heterogeneous expression).1 To study why anti-tumor immunity is reduced in a heterogeneous setting we developed a transplant murine tumor model engineered to express neoantigens in a heterogeneous pattern or homogenously.MethodsA curated list of neoantigens with varying predicted MCHI binding affinities was used to established an array of cell lines expressing at one to three neoantigens. The lines were inoculated subcutaneously in immunocompetent mice as mixtures (heterogenous) or as a single line (homogenous) to study the resulting immune response. Tumors were harvested at days 7, 10 and 14 and flow cytometry analysis was used to phenotype infiltrating immune populations, including antigen-specific CD8+ T cells. ELISpot assays were performed using splenocytes from the same timepoints to determine the frequency of antigen-specific T cells in the periphery.ResultsCompared to neoantigens predicted to bind weakly to MHCI, neoantigens predicted to bind strongly elicited robust expansion of antigen-specific T cells in the periphery and tumors expressing these antigens alone exhibited greater numbers of tumor infiltrating T cells. Homogenous expression of two neoantigens was found to enhance anti-tumor immunity by increasing the frequency of tumor-reactive T cells. Further, homogenous expression of two neoantigens induced protective immunity against antigens, including those that failed to be controlled when expressed alone.ConclusionsUsing our novel reductionist tumor model, our results suggest that a more robust response against weak antigens could be induced if a response against a strong, highly immunogenic neoantigen is mounted simultaneously. This observation has direct implications for the design of neoantigen vaccines either as mono- or combination immunotherapies, especially in the setting of a heterogeneous neoantigen expression pattern.ReferencesMcGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TB, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, Swanton C. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016 Mar 25;351(6280):1463–9.

Interleukin-10–Treated Human Dendritic Cells Induce a Melanoma-Antigen–Specific Anergy in CD8+ T Cells Resulting in a Failure to Lyse Tumor Cells

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1634-1642 ◽  
Author(s):  
Kerstin Steinbrink ◽  
Helmut Jonuleit ◽  
Gabriele Müller ◽  
Gerold Schuler ◽  
Jürgen Knop ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Line ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Specific Antigen ◽  
Interleukin 10 ◽  
Tumor Rejection ◽  
Anergic T Cells

Dendritic cells (DC) are critically involved in the initiation of primary immune processes, including tumor rejection. In our study, we investigated the effect of interleukin-10 (IL-10)–treated human DC on the properties of CD8+ T cells that are known to be essential for the destruction of tumor cells. We show that IL-10–pretreatment of DC not only reduces their allostimulatory capacity, but also induces a state of alloantigen-specific anergy in both primed and naive (CD45RA+) CD8+ T cells. To investigate the influence of IL-10–treated DC on melanoma-associated antigen-specific T cells, we generated a tyrosinase-specific CD8+ T-cell line by several rounds of stimulation with the specific antigen. After coculture with IL-10–treated DC, restimulation of the T-cell line with untreated, antigen-pulsed DC demonstrated peptide-specific anergy in the tyrosinase-specific T cells. Addition of IL-2 to the anergic T cells reversed the state of both alloantigen- or peptide-specific anergy. In contrast to optimally stimulated CD8+ T cells, anergic tyrosinase-specific CD8+ T cells, after coculture with peptide-pulsed IL-10–treated DC, failed to lyse an HLA-A2–positive and tyrosinase-expressing melanoma cell line. Thus, our data demonstrate that IL-10–treated DC induce an antigen-specific anergy in cytotoxic CD8+ T cells, a process that might be a mechanism of tumors to inhibit immune surveillance by converting DC into tolerogenic antigen-presenting cells.

A combined local treatment with anti-PD-1 antibody and bone marrow derived dendritic cells after x-ray irradiation to subcutaneous melanoma in a murine model.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14541-e14541
Author(s):  
Yuzi Wang ◽  
Lue Sun ◽  
Xiaokang Li ◽  
Koji Tsuboi
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Combination Treatment ◽  
Bone Marrow Cells ◽  
Local Treatment ◽  
Activated T Cells ◽  
X Ray

e14541 Background: In situ dying and just died tumor cells after irradiation give danger signals and release tumor-specific antigens which are supposed to be incorporated into dendritic cells (DCs), and sequentially rendering T-cells activated and proliferated. However, it has been clarified that activated T-cells are killed by PD-L1 ligands on tumor cells which bind to PD-1 receptors on T-cells, consequently suppressing systemic cellular immunological response. To improve local control and prevent metastases after localized radiotherapy, we examined whether the combination of anti-PD-1 antibody and bone marrow derived DCs (BM-DCs) can enhance both the local and systemic antitumor immunoreactions after localized X-ray irradiation in a murine melanoma model. Methods: BM-DCs were induced by using GM-CSF and IL-4 from bone marrow cells taken from the femur and tibia of C57BL/6 mice. Syngeneic B16 melanoma cells implanted subcutaneously at the left thighs of C57BL/6 mice were irradiated with X-ray (8 Gy) 5 days after inoculation. After 1, 3, 5, 7 days from irradiation, induced DCs were injected directly to the tumor site, similarly, after 1, 3, 5 days from irradiation, anti-PD-1 antibody were injected intraperitoneally. To examine the systemic immunoreaction, B16 cells were also inoculated to the right side 4 days after the left side inoculation, and treated with the same protocols only on the left side. The size of tumors was monitored and survival analyses were performed. Results: The induced DCs showed the ability to incorporate antigens and to prime and proliferate T-cells in vitro. The combination treatment of anti-PD-1 antibody, BM-DCs and X-ray irradiation showed a significant delay of tumor growth compared to single or double combination treatments in vivo. In addition, this triple combination treatment significantly inhibited the tumor growth on the other side compared to other treatments. Conclusions: DCs and anti-PD-1 antibody significantly enhanced the antitumor effect of X-ray irradiation and prolonged the survival time. This combination also can induce a strong systemic antitumor immunoreaction which could treat metastatic tumors.

CXCR4 antagonist (BL-8040) to enhance antitumor effects by increasing tumor infiltration of antigen-specific effector T-cells.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 73-73 ◽  
Author(s):  
Pankaj Gaur ◽  
Vivek Verma ◽  
Seema Gupta ◽  
Ella Sorani ◽  
Abi Vainstein Haras ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Growth ◽  
Progenitor Cells ◽  
Specific Antigen ◽  
Mouse Tumor ◽  
Cxcr4 Antagonist ◽  
Antitumor Effects ◽  
Hematopoietic Stem ◽  
Effector Cells

73 Background: C-X-C chemokine receptor type 4 (CXCR4) helps to retain the hematopoietic stem cells (HSC) in the bone marrow (BM). CXCR4 binds to its ligand CXCL12/SDF1 which is constitutively expressed in the BM thereby inhibiting the mobilization of CXCR4 expressing immune progenitor cells. Moreover, increased numbers of effector cells in the tumor microenvironment (TME) are directly correlated to enhanced immunotherapeutic efficacy. Therefore, we hypothesized that CXCR4 antagonism will result in movement of immune progenitor cells from BM to periphery leading to increased availability of T-cells in the periphery and better infiltration of effector cells into the TME. Methods: In TC-1 mouse tumor-model, we tested the effects of CXCR4 antagonist (BL-8040; 4 doses; 24 h apart; 20 mg/kg) on the tumor growth and mice survival in the presence of tumor-specific antigen priming using E7 peptide vaccine (3 doses, one week apart). Anti-tumor immune responses were determined in the tumor tissues obtained 3-4 days after the second vaccination using flow cytometry. Results: We found that BL-8040 given with specific antigenic stimulation results in significantly enhanced anti-tumor immune response, leading to a decrease in tumor growth (p≤0.001 at day 21) and prolonged mice survival. At day 35 after tumor implantation, 80% of mice survived in the BL-8040 + vaccine treatment group compared to 0% survival following BL-8040 or vaccine treatments. Interestingly, we also found that BL-8040 leads to a significant increase in the numbers of antigen-specific CD8+ T-cells in the TME. We also found that starting BL-8040 prior to or together with the priming of the mice did not affect the outcome, suggesting that the scheduling of BL-8040 does not affect the therapeutic outcomes. Conclusions: These results suggest that BL-8040 treatment enhances anti-tumor immune response by potentially increasing the immune progenitor cells in the periphery leading to a better immune response. These results also suggest that BL-8040, a CXCR4 antagonist, is a promising immune-modulatory agent with potent anti-tumor effects.

scholarly journals Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti–PD-1 treatment

2018 ◽  
Vol 115 (17) ◽  
pp. E4041-E4050 ◽  
Author(s):  
Elisa Peranzoni ◽  
Jean Lemoine ◽  
Lene Vimeux ◽  
Vincent Feuillet ◽  
Sarah Barrin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Close Contact ◽  
Tumor Model ◽  
Tumor Stroma ◽  
Dynamic Imaging ◽  
Mouse Tumor ◽  
T Cell Migration

In a large proportion of cancer patients, CD8 T cells are excluded from the vicinity of cancer cells. The inability of CD8 T cells to reach tumor cells is considered an important mechanism of resistance to cancer immunotherapy. We show that, in human lung squamous-cell carcinomas, exclusion of CD8 T cells from tumor islets is correlated with a poor clinical outcome and with a low lymphocyte motility, as assessed by dynamic imaging on fresh tumor slices. In the tumor stroma, macrophages mediate lymphocyte trapping by forming long-lasting interactions with CD8 T cells. Using a mouse tumor model with well-defined stromal and tumor cell areas, macrophages were depleted with PLX3397, an inhibitor of colony-stimulating factor-1 receptor (CSF-1R). Our results reveal that a CSF-1R blockade enhances CD8 T cell migration and infiltration into tumor islets. Although this treatment alone has minor effects on tumor growth, its combination with anti–PD-1 therapy further increases the accumulation of CD8 T cells in close contact with malignant cells and delays tumor progression. These data suggest that the reduction of macrophage-mediated T cell exclusion increases tumor surveillance by CD8 T cells and renders tumors more responsive to anti–PD-1 treatment.

scholarly journals Integrin αvβ8 on T cells is responsible for suppression of anti-tumor immunity in multiple syngeneic models and is a promising target for tumor immunotherapy

2020 ◽  
Author(s):  
Eswari Dodagatta-Marri ◽  
Hsiao-Yen Ma ◽  
Benjia Liang ◽  
John Li ◽  
Dominique S. Meyer ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Immune Checkpoint Blockade ◽  
Complete Regression ◽  
Promising Target

AbstractThe αvβ8 integrin is a key activator of transforming growth factor β (TGF β), which has been shown to inhibit anti-tumor immunity. Previous work has suggested that αvβ8 on tumor cells could modulate tumor growth and responses to immune checkpoint blockade. We now show that a potent blocking monoclonal antibody against αvβ8 (ADWA-11) causes growth suppression or complete regression in syngeneic models of squamous cell carcinoma (CCK168), mammary cancer (EMT-6), colon cancer (CT26), and prostate cancer (TRAMPC2), especially when it is combined with other immunomodulators (anti-PD-1, anti-CTLA-4 or 4-1BB) or radiotherapy. αvβ8 is expressed on tumor cells in some of these models, but tumor cell expression of αvβ8 is not essential for the beneficial effects of ADWA-11 therapy. αvβ8 is consistently expressed at highest levels on CD4+CD25+ T cells within tumors, and specific deletion of Itgb8 from T cells is as effective as ADWA-11 in suppressing tumor growth. Treatment with ADWA-11 increases expression of a suite of genes in tumor infiltrating CD8+ T cells that are normally inhibited by TGFβ and are involved in tumor cell killing, including Granzyme B and Interferon-γ. These findings solidify αvβ8 integrin as a promising target for cancer immunotherapy, even for tumors that do not express this integrin.

Interleukin-10–Treated Human Dendritic Cells Induce a Melanoma-Antigen–Specific Anergy in CD8+ T Cells Resulting in a Failure to Lyse Tumor Cells

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1634-1642 ◽  
Author(s):  
Kerstin Steinbrink ◽  
Helmut Jonuleit ◽  
Gabriele Müller ◽  
Gerold Schuler ◽  
Jürgen Knop ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Line ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Specific Antigen ◽  
Interleukin 10 ◽  
Tumor Rejection ◽  
Anergic T Cells

Abstract Dendritic cells (DC) are critically involved in the initiation of primary immune processes, including tumor rejection. In our study, we investigated the effect of interleukin-10 (IL-10)–treated human DC on the properties of CD8+ T cells that are known to be essential for the destruction of tumor cells. We show that IL-10–pretreatment of DC not only reduces their allostimulatory capacity, but also induces a state of alloantigen-specific anergy in both primed and naive (CD45RA+) CD8+ T cells. To investigate the influence of IL-10–treated DC on melanoma-associated antigen-specific T cells, we generated a tyrosinase-specific CD8+ T-cell line by several rounds of stimulation with the specific antigen. After coculture with IL-10–treated DC, restimulation of the T-cell line with untreated, antigen-pulsed DC demonstrated peptide-specific anergy in the tyrosinase-specific T cells. Addition of IL-2 to the anergic T cells reversed the state of both alloantigen- or peptide-specific anergy. In contrast to optimally stimulated CD8+ T cells, anergic tyrosinase-specific CD8+ T cells, after coculture with peptide-pulsed IL-10–treated DC, failed to lyse an HLA-A2–positive and tyrosinase-expressing melanoma cell line. Thus, our data demonstrate that IL-10–treated DC induce an antigen-specific anergy in cytotoxic CD8+ T cells, a process that might be a mechanism of tumors to inhibit immune surveillance by converting DC into tolerogenic antigen-presenting cells.

scholarly journals Murine hepatoma treatment with mature dendritic cells stimulated by Trichinella spiralis excretory/secretory products

Parasite ◽  
2020 ◽  
Vol 27 ◽  
pp. 47
Author(s):  
Jing Ding ◽  
Xiaolei Liu ◽  
Bin Tang ◽  
Xue Bai ◽  
Yang Wang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Tumor Growth ◽  
Antitumor Effect ◽  
Trichinella Spiralis ◽  
Critical Role ◽  
Tumor Model ◽  
Control Group ◽  
Tumor Inhibition ◽  
Significant Difference ◽  
Secretory Products

Excretory/Secretory Products (ESPs) of the nematode Trichinella spiralis contain antitumor-active substances that inhibit tumor growth. Mature dendritic cells (DCs) play a critical role in the antitumor immunity of the organism. As pathogen-derived products, it ought to be discussed whether T. spiralis ESPs will reduce the antitumor effect of mature DCs from the host before it is applied to patients’ tumors. Therefore, the aim of this work was to evaluate the immunological effect of DCs stimulated by T. spiralis ESPs in H22 tumor-bearing mice. H22 tumor model mice in this study were randomly divided into four groups according to the treatment: PBS control group, ESP group, DCs group, and DCs stimulated with T. spiralis ESP (ESP+DCs group). The antitumor effect was evaluated by tumor inhibition rate and cytokine detection using ELISA. The results showed significant inhibition in tumor growth in the ESP+DCs, DCs and ESP groups when compared with the PBS control group (p < 0.01, p < 0.01, and p < 0.05, respectively). However, no significant difference was observed on tumor inhibition rates between the ESP+DCs and DCs groups. The decrease in IL-4, IL-6, and IL-10, and the increase in IFN-γ between the DCs and ESP+DCs groups were also not significant. Therefore, DCs stimulated by ESP did not reduce the antitumor effect of mature DCs, which demonstrated that the T. spiralis ESP would not affect the antitumor effect of mature DCs by modulating the immune response of the host, and that ESPs are safe in antitumor immunology when applied in a tumor model mice.

scholarly journals Cellular cytotoxicity is a form of immunogenic cell death

2020 ◽  
Vol 8 (1) ◽  
pp. e000325 ◽  
Author(s):  
Luna Minute ◽  
Alvaro Teijeira ◽  
Alfonso R Sanchez-Paulete ◽  
Maria C Ochoa ◽  
Maite Alvarez ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Dendritic Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Immunogenic Cell Death ◽  
Cell Debris ◽  
Tumor Cell Death ◽  
Mhc Multimer

BackgroundThe immune response to cancer is often conceptualized with the cancer immunity cycle. An essential step in this interpretation is that antigens released by dying tumors are presented by dendritic cells to naive or memory T cells in the tumor-draining lymph nodes. Whether tumor cell death resulting from cytotoxicity, as mediated by T cells or natural killer (NK) lymphocytes, is actually immunogenic currently remains unknown.MethodsIn this study, tumor cells were killed by antigen-specific T-cell receptor (TCR) transgenic CD8 T cells or activated NK cells. Immunogenic cell death was studied analyzing the membrane exposure of calreticulin and the release of high mobility group box 1 (HMGB1) by the dying tumor cells. Furthermore, the potential immunogenicity of the tumor cell debris was evaluated in immunocompetent mice challenged with an unrelated tumor sharing only one tumor-associated antigen and by class I major histocompatibility complex (MHC)-multimer stainings. Mice deficient inBatf3,Ifnar1andSting1were used to study mechanistic requirements.ResultsWe observe in cocultures of tumor cells and effector cytotoxic cells, the presence of markers of immunogenic cell death such as calreticulin exposure and soluble HMGB1 protein. Ovalbumin (OVA)-transfected MC38 colon cancer cells, exogenously pulsed to present the gp100 epitope are killed in culture by mouse gp100-specific TCR transgenic CD8 T cells. Immunization of mice with the resulting destroyed cells induces epitope spreading as observed by detection of OVA-specific T cells by MHC multimer staining and rejection of OVA+EG7 lymphoma cells. Similar results were observed in mice immunized with cell debris generated by NK-cell mediated cytotoxicity. Mice deficient inBatf3-dependent dendritic cells (conventional dendritic cells type 1, cDC1) fail to develop an anti-OVA response when immunized with tumor cells killed by cytotoxic lymphocytes. In line with this, cultured cDC1 dendritic cells uptake and can readily cross-present antigen from cytotoxicity-killed tumor cells to cognate CD8+T lymphocytes.ConclusionThese results support that an ongoing cytotoxic antitumor immune response can lead to immunogenic tumor cell death.

TIGIT Induces (CD3+) T Cell Dysfunction by Inhibiting Glucose Metabolism and its Reversal by TIGIT and/or PD-1 Blockade in Colorectal Cancer

2021 ◽  
Author(s):  
qi shao ◽  
Lei Wang ◽  
maoling yuan ◽  
Xiaohong Jin ◽  
changping wu
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Peripheral Blood ◽  
Cancer Tissue ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Abstract Background: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immunosuppressive receptor expressed on the surface of immune cells, suppressing immune responses by activating the intracellular negative regulatory signals. TIGIT plays an important role in the pathogenesis of various tumors, but its immune escape in colorectal cancer remains unclear.Methods: In this study, TIGIT expression in the peripheral blood and tissue microarrays was detected flow cytometry and immunofluorescence and its relationship with prognosis was evaluated. The proliferation and cytokines of TIGIT+ T cells were measured. Glucose metabolism and key enzymes were detected by qPCR or western blot. After establishing the co-cultured system and xenotransplant models, TIGIT antibody alone or combined with PD-1 antibody was blocked to observe the tumor growth.Results: We found that the proportion of CD3+TIGIT+ T cells was increased in peripheral blood and cancer tissue in colorectal cancer patients when compared with the healthy donors. These cells exhibited functional defects, low proliferative activity, impaired cytokine production and reduced glucose metabolism. A strong association was also observed between the elevated TIGIT expression and poor prognosis. In the in vitro co-culture assays of T cells and tumor cells, the suppressed glucose metabolic activity of T cells was reversed by TIGIT blockade. In addition, this blockade induced the apoptosis and reduced G2/M transit in tumor cells. The antitumor efficacy of TIGIT Ab therapy was further demonstrated in a human colorectal xenograft mice model while co-blockers of TIGIT and PD-1 exhibited synergistic suppressing effects on tumor growth.Conclusions: It is suggest that while TIGIT induces CD3+ T cell dysfunction in colorectal cancer, co-targeting TIGIT and PD-1 can lead to an effective antitumor response and may serve as a novel therapeutic strategy for colorectal patients.

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