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.

SOX2 as a target for immunotherapy of pediatric gliomas.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e22012-e22012 ◽  
Author(s):  
Juan Vasquez ◽  
Anita Huttner ◽  
Lin Zhang ◽  
Asher Marks ◽  
Amy Chan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Cell Mass ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Low Grade ◽  
Glial Tumors

e22012 Background: New treatments are needed to improve outcomes for pediatric gliomas. Immune checkpoint inhibitors are effective therapies in tumors with a high mutation burden that express multiple neo-antigens. However, for pediatric tumors that carry few mutations, there is a need to identify new antigenic targets of anti-tumor immunity. SOX2 is an embryonal stem cell antigen implicated in the biology of glioma initiating cells. Expression of SOX2 by pediatric glial tumors, and the capacity of the immune system in these patients to recognize SOX2, has not been studied. Methods: We examined the expression of SOX2 on paraffin-embedded tissue from pediatric glial tumors (n = 30). The presence of T cell immunity to SOX2 was examined in both blood and tumor-infiltrating T cells using antigen-dependent cytokine and T cell proliferation assays (n = 15). The nature of tumor-infiltrating immune cells in glial tumors (n = 4) was analyzed using single cell mass cytometry. Results: SOX2 is expressed by tumor cells but not surrounding normal tissue in all low grade gliomas (n = 15), high grade gliomas (n = 7), ependymomas (n = 3) and in 60% of oligodendrogliomas (n = 5). T cells against SOX2 can be detected in blood and tumor tissue in 33% of patients. CD4 and CD8 tumor infiltrating T-cells display a higher proportion of PD-1 expression compared to circulating T cells (p < 0.05). Glial CD4 and CD8 T cells are enriched for tissue resident memory phenotype (TRM; CD45RO+, CD69+, CCR7-) and the expression of PD-1 is primarily on these TRM cells (p < 0.05). A subset of CD4 and CD8 TRM cells also co-express multiple inhibitory checkpoints including PD-L1 and TIGIT. Glial tumors also contain NK cells with reduced expression of lytic granzyme (p < 0.05). Conclusions: Our data demonstrate in vivo immunogenicity of SOX2, which is specifically overexpressed on pediatric glial tumor cells. Our data also suggest that the TRM subset of tumor-infiltrating T cells may be key targets for immune checkpoint blockade, and harnessing tumor immunity will likely require the combined targeting of multiple inhibitory checkpoints. Future efforts to target SOX2 with dendritic cell vaccines combined with immune checkpoint blockade could provide effective tumor immunity and improve outcomes in pediatric brain tumors.

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.

scholarly journals The CCR2/MCP-1 Chemokine Pathway and Lung Adenocarcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3723
Author(s):  
Payal Mittal ◽  
Liqing Wang ◽  
Tatiana Akimova ◽  
Craig A. Leach ◽  
Jose C. Clemente ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Suppressor Cells ◽  
Treg Cells ◽  
Cancer Models ◽  
Inflammatory Site ◽  
Ccr2 Antagonist

Host anti-tumor immunity can be hindered by various mechanisms present within the tumor microenvironment, including the actions of myeloid-derived suppressor cells (MDSCs). We investigated the role of the CCR2/MCP-1 pathway in MDSC-associated tumor progression in murine lung cancer models. Phenotypic profiling revealed maximal expression of CCR2 by tumor-resident MDSCs, and MCP-1 by transplanted TC1 tumor cells, respectively. Use of CCR2-knockout (CCR2-KO) mice showed dependence of tumor growth on CCR2 signaling. Tumors in CCR2-KO mice had fewer CCR2low MDSCs, CD4 T cells and Tregs than WT mice, and increased infiltration by CD8 T cells producing IFN-γ and granzyme-B. Effects were MDSC specific, since WT and CCR2-KO conventional T (Tcon) cells had comparable proliferation and production of inflammatory cytokines, and suppressive functions of WT and CCR2-KO Foxp3+ Treg cells were also similar. We used a thioglycolate-induced peritonitis model to demonstrate a role for CCR2/MCP-1 in trafficking of CCR2+ cells to an inflammatory site, and showed the ability of a CCR2 antagonist to inhibit such trafficking. Use of this CCR2 antagonist promoted anti-tumor immunity and limited tumor growth. In summary, tumor cells are the prime source of MCP-1 that promotes MDSC recruitment, and our genetic and pharmacologic data demonstrate that CCR2 targeting may be an important component of cancer immunotherapy.

scholarly journals A tumor-specific mechanism of Treg enrichment mediated by the integrin αvβ8

2021 ◽  
Vol 6 (57) ◽  
pp. eabf0558
Author(s):  
Robert I. Seed ◽  
Kenji Kobayashi ◽  
Saburo Ito ◽  
Naoki Takasaka ◽  
Anthony Cormier ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Specific Mechanism ◽  
Tumor Immune Evasion ◽  
Geometrically Constrained ◽  
And Diffusion

Regulatory T cells (Tregs) that promote tumor immune evasion are enriched in certain tumors and correlate with poor prognosis. However, mechanisms for Treg enrichment remain incompletely understood. We described a mechanism for Treg enrichment in mouse and human tumors mediated by the αvβ8 integrin. Tumor cell αvβ8 bound to latent transforming growth factor–β (L–TGF-β) presented on the surface of T cells, resulting in TGF-β activation and immunosuppressive Treg differentiation in vitro. In vivo, tumor cell αvβ8 expression correlated with Treg enrichment, immunosuppressive Treg gene expression, and increased tumor growth, which was reduced in mice by αvβ8 inhibition or Treg depletion. Structural modeling and cell-based studies suggested a highly geometrically constrained complex forming between αvβ8-expressing tumor cells and L–TGF-β–expressing T cells, facilitating TGF-β activation, independent of release and diffusion, and providing limited access to TGF-β inhibitors. These findings suggest a highly localized tumor-specific mechanism for Treg enrichment.

scholarly journals AGI-134: a fully synthetic α-Gal glycolipid that converts tumors into in situ autologous vaccines, induces anti-tumor immunity and is synergistic with an anti-PD-1 antibody in mouse melanoma models

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Stephen M. Shaw ◽  
Jenny Middleton ◽  
Kim Wigglesworth ◽  
Amber Charlemagne ◽  
Oliver Schulz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Tumor Antigen ◽  
Tumor Regression ◽  
Antigen Uptake

Abstract Background Treatments that generate T cell-mediated immunity to a patient’s unique neoantigens are the current holy grail of cancer immunotherapy. In particular, treatments that do not require cumbersome and individualized ex vivo processing or manufacturing processes are especially sought after. Here we report that AGI-134, a glycolipid-like small molecule, can be used for coating tumor cells with the xenoantigen Galα1-3Galβ1-4GlcNAc (α-Gal) in situ leading to opsonization with pre-existing natural anti-α-Gal antibodies (in short anti-Gal), which triggers immune cascades resulting in T cell mediated anti-tumor immunity. Methods Various immunological effects of coating tumor cells with α-Gal via AGI-134 in vitro were measured by flow cytometry: (1) opsonization with anti-Gal and complement, (2) antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells, and (3) phagocytosis and antigen cross-presentation by antigen presenting cells (APCs). A viability kit was used to test AGI-134 mediated complement dependent cytotoxicity (CDC) in cancer cells. The anti-tumoral activity of AGI-134 alone or in combination with an anti-programmed death-1 (anti-PD-1) antibody was tested in melanoma models in anti-Gal expressing galactosyltransferase knockout (α1,3GT−/−) mice. CDC and phagocytosis data were analyzed by one-way ANOVA, ADCC results by paired t-test, distal tumor growth by Mantel–Cox test, C5a data by Mann–Whitney test, and single tumor regression by repeated measures analysis. Results In vitro, α-Gal labelling of tumor cells via AGI-134 incorporation into the cell membrane leads to anti-Gal binding and complement activation. Through the effects of complement and ADCC, tumor cells are lysed and tumor antigen uptake by APCs increased. Antigen associated with lysed cells is cross-presented by CD8α+ dendritic cells leading to activation of antigen-specific CD8+ T cells. In B16-F10 or JB/RH melanoma models in α1,3GT−/− mice, intratumoral AGI-134 administration leads to primary tumor regression and has a robust abscopal effect, i.e., it protects from the development of distal, uninjected lesions. Combinations of AGI-134 and anti-PD-1 antibody shows a synergistic benefit in protection from secondary tumor growth. Conclusions We have identified AGI-134 as an immunotherapeutic drug candidate, which could be an excellent combination partner for anti-PD-1 therapy, by facilitating tumor antigen processing and increasing the repertoire of tumor-specific T cells prior to anti-PD-1 treatment.

scholarly journals Knockout of High-Mobility Group Box 1 in B16F10 Melanoma Cells Induced Host Immunity-Mediated Suppression of In Vivo Tumor Growth

2021 ◽  
Author(s):  
Kanako Yokomizo ◽  
Kayoko Waki ◽  
Miyako Ozawa ◽  
Keiko Yamamoto ◽  
Sachiko Ogasawara ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
High Mobility

Abstract High mobility group box 1 (HMGB1) has been reported as a damage-associated molecular pattern (DAMP) molecule that is released from damaged or dead cells and induces inflammation and subsequent innate immunity. However, the role of HMGB1 in the anti-tumor immunity is unclear since inflammation in the tumor microenvironment also contributes to tumor promotion and progression. In the present study, we established HMGB1-knockout clones from B16F10 and CT26 murine tumors by genome editing using the CRISPR/Cas9 system and investigated the role of HMGB1 in anti-tumor immunity. We found that 1) knockout of HMGB1 in the tumor cells suppressed in vivo, but not in vitro, tumor growth, 2) the suppression of the in vivo tumor growth was mediated by CD8 T cells, and 3) infiltration of CD8 T cells, macrophages and dendritic cells into the tumor tissues was accelerated in HMGB1-knockout tumors. These results demonstrated that knockout of HMGB1 in tumor cells converted tumors from poor infiltration of immune cells called “cold” to “immune-inflamed” or “hot” and inhibited in vivo tumor growth mediated by cytotoxic T lymphocytes. Infiltration of immune cells to the tumor microenvironment is an important step in the series known as the cancer immunity cycle. Thus, manipulation of tumor-derived HMGB1 might be applicable to improve the clinical outcomes of cancer immunotherapies, including immune checkpoint blockades and cancer vaccine therapies.

scholarly journals Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models

2021 ◽  
Vol 13 (606) ◽  
pp. eabd1616
Author(s):  
Amaia Martinez-Usatorre ◽  
Ece Kadioglu ◽  
Gael Boivin ◽  
Chiara Cianciaruso ◽  
Alan Guichard ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Antiangiogenic Therapy ◽  
Transforming Growth Factor Β ◽  
Immune Checkpoint Blockade ◽  
Genetically Engineered ◽  
Mouse Tumor ◽  
Longitudinal Imaging

Immune checkpoint blockade (ICB) with PD-1 or PD-L1 antibodies has been approved for the treatment of non–small cell lung cancer (NSCLC). However, only a minority of patients respond, and sustained remissions are rare. Both chemotherapy and antiangiogenic drugs may improve the efficacy of ICB in mouse tumor models and patients with cancer. Here, we used genetically engineered mouse models of KrasG12D/+;p53−/− NSCLC, including a mismatch repair–deficient variant (KrasG12D/+;p53−/−;Msh2−/−) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, antiangiogenic therapy, and chemotherapy. Antiangiogenic blockade of vascular endothelial growth factor A and angiopoietin-2 markedly slowed progression of autochthonous lung tumors, but contrary to findings in other cancer types, addition of a PD-1 or PD-L1 antibody was not beneficial and even accelerated progression of a fraction of the tumors. We found that antiangiogenic treatment facilitated tumor infiltration by PD-1+ regulatory T cells (Tregs), which were more efficiently targeted by the PD-1 antibody than CD8+ T cells. Both tumor-associated macrophages (TAMs) of monocyte origin, which are colony-stimulating factor 1 receptor (CSF1R) dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establish a transforming growth factor–β–rich tumor microenvironment that supported PD-1+ Tregs. Dual TAM targeting with a combination of a CSF1R inhibitor and cisplatin abated Tregs, redirected the PD-1 antibody to CD8+ T cells, and improved the efficacy of antiangiogenic immunotherapy, achieving regression of most tumors.

scholarly journals Oncolytic vaccinia virus delivering tethered IL-12 enhances antitumor effects with improved safety

2020 ◽  
Vol 8 (1) ◽  
pp. e000710 ◽  
Author(s):  
Yan Ge ◽  
Haiyan Wang ◽  
Jinghua Ren ◽  
Weilin Liu ◽  
Lingjuan Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Vaccinia Virus ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Immune Checkpoint Blockade ◽  
Oncolytic Viruses ◽  
Interleukin 12 ◽  
Antitumor Effects ◽  
Positive Effects

Immune checkpoint blockade is arguably the most effective current cancer therapy approach; however, its efficacy is limited to patients with “hot” tumors, warranting an effective approach to transform “cold” tumors. Oncolytic viruses (especially properly armed ones) have positive effects on almost every aspect of the cancer–immunity cycle and can change the cancer–immune set point of a tumor. Here, we tested whether oncolytic vaccinia virus delivering tethered interleukin 12 (IL-12) could turn a “cold” tumor into a “hot” tumor while avoiding IL-12’s systemic toxicity. Our data demonstrated that tethered IL-12 could be maintained in the tumor without treatment-induced toxic side effects. Moreover, the treatment facilitated tumor infiltration of more activated CD4+and CD8+T cells and less Tregs, granulocytic myeloid-derivedsuppressor cells, and exhausted CD8+T cells, with increased interferon γ and decreased transforming growth factor β, cyclooxygenase-2, and vascular endothelial growth factor expression, leading to transformed, immunogenic tumors and improved survival. Combined with programmed cell death 1 blockade, vaccinia virus expressing tethered IL-12 cured all mice with late-stage colon cancer, suggesting immediate translatability to the clinic.

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.

Integrin αvβ8 on T Cells is Responsible for Suppression of Anti-Tumor Immunity in 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 Immunity ◽  
Tumor Immunotherapy ◽  
Promising Target
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