Intracellular Bacterial Vectors That Induce CD8+ T Cells with Similar Cytolytic Abilities but Disparate Memory Phenotypes Provide Contrasting Tumor Protection

Stark, Felicity C.; Sad, Subash; Krishnan, Lakshmi

doi:10.1158/0008-5472.can-08-3160

Cited by 35 publications

(28 citation statements)

References 47 publications

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“…to C57BL/6 mice with established B16-OVA melanoma and followed the tumor progression over time. Consistent with published work (17), LM-OVA led to enhanced tumor control and 25% eradication compared with LM-GP33-treated mice (Fig. 2C).…”

Section: Resultssupporting

confidence: 92%

Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors

Schauder

Jing

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Because of insufficient migration and antitumor function of transferred T cells, especially inside the immunosuppressive tumor microenvironment (TME), the efficacy of adoptive cell transfer (ACT) is much curtailed in treating solid tumors. To overcome these challenges, we sought to reenergize ACT (ReACT) with a pathogen-based cancer vaccine. To bridge ACT with a pathogen, we genetically engineered tumor-specific CD8 T cells in vitro with a second T-cell receptor (TCR) that recognizes a bacterial antigen. We then transferred these dual-specific T cells in combination with intratumoral bacteria injection to treat solid tumors in mice. The dual-specific CD8 T cells expanded vigorously, migrated to tumor sites, and robustly eradicated primary tumors. The mice cured from ReACT also developed immunological memory against tumor rechallenge. Mechanistically, we have found that this combined approach reverts the immunosuppressive TME and recruits CD8 T cells with an increased number and killing ability to the tumors.doptive cell transfer (ACT) of genetically engineered T cells has become a promising cancer immunotherapy for hematologic malignancies (1-4). However, the efficacy of such an approach is curtailed when treating solid tumors (2, 5, 6). The primary hurdles that must be overcome for ACT to be effective against solid tumors include inadequate responses of adoptively transferred T cells, especially in dealing with heterogeneous cancerous cells that bear a wide range of tumor-associated antigens (TAAs) (2, 6); reduced migration of adoptively transferred T cells into the tumor (7); and the immunosuppressive microenvironment within tumors that often induces a rapid loss of T-cell effector function (8).Using infectious pathogens that stimulate a patient's immune system and break immunosuppression in the tumor microenvironment is a century-old strategy that is now being rejuvenated to enhance cancer immunotherapy (9). Bacillus Calmette-Guérin (bacillus Calmette-Guérin), a live attenuated strain of Mycobacterium bovis, has been widely used in treating bladder cancer and melanoma for decades (10, 11). Although effective, bacillus CalmetteGuérin only induces transient and nonspecific antitumor immune responses. To generate a tumor-specific T-cell response, recombinant Listeria monocytogenes (LM) expressing TAAs has recently been developed and shown promising results in treating multiple cancers including breast and pancreatic cancer (9). Owing to the heterogeneity of tumor cells, it remains challenging for recombinant LM-based immunotherapies targeting a single TAA to provide durable and complete regression of cancer because cancer cells that do not express the targeted TAA are able to evade immunosurveillance (2,6,7,9). Thus, there is a critical need for new strategies that generate robust T-cell responses with broad coverage of tumor antigens to improve pathogen-based cancer vaccines.To overcome these hurdles and induce a vigorous antitumor T-cell response, we sought to combine the strength of ACT and pathogen-based can...

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Section: Resultssupporting

confidence: 92%

Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors

Schauder

Jing

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Also, these bacteria are often used in combination with traditional methods such as radiation (4) and chemotherapy (25) for cancer therapy. Bacteria per se can stimulate immune responses (22) and secrete potential antitumor substances, DNA fragments, and other compounds that further improve the therapeutic effects (17,26). Therefore, interaction between bacteria and tumor cells and their antitumor effects have been extensively studied in recent years (9,12,43).…”

mentioning

confidence: 99%

Escherichia coli Nissle 1917 Targets and Restrains Mouse B16 Melanoma and 4T1 Breast Tumors through Expression of Azurin Protein

Zhang

Xia

et al. 2012

Appl Environ Microbiol

108

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Many studies have demonstrated that intravenously administered bacteria can target and proliferate in solid tumors and then quickly be released from other organs. Here, we employed the tumor-targeting property of Escherichia coli Nissle 1917 to inhibit mouse B16 melanoma and 4T1 breast tumors through the expression of azurin protein. For this purpose, recombinant azurinexpressing E. coli Nissle 1917 was developed. The levels of in vitro and in vivo azurin secretion in the engineered bacterium were determined by immunochemistry. Our results demonstrated that B16 melanoma and orthotopic 4T1 breast tumor growth were remarkably restrained and pulmonary metastasis was prevented in immunocompetent mice. It is worth noting that this therapeutic effect partially resulted from the antitumor activity of neutrophils and lymphocytes due to inflammatory responses caused by bacterial infections. No toxicity was observed in the animal during the experiments. This study indicates that E. coli Nissle 1917 could be a potential carrier to deliver antitumor drugs effectively for cancer therapy.

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“…While decreased CD62L expression on CD8 + T cells is associated with both effector and effector memory phenotypes and an overall increase in cytotoxicity, a predominantly CD62L high CD8 + T cell population has been associated with central memory and increased re-call CD8 + T cell proliferation and efficacious anti-tumor response [26]. After one vaccination of MS-OVA or LM-OVA causing an initial (day 7) induction of CD62L low effector CD8 + T cells, there was a subsequent gradual increase in CD62L high memory cells.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to generating a higher number of tumor specific CD8 + T cells, the memory phenotype is thought to be important for the overall anti-tumor immune response [26]. Previously, we have shown that when memory OVA-specific CD8 + T cell frequencies are similar and CD62L expression is low or their ligand is absent, long lasting tumor protection is impaired [26,35].…”

Section: Discussionmentioning

confidence: 99%

“…In choosing a vaccine model to compare with archaeosomes, we selected a live vaccine Listeria monocytogenes expressing OVA (LM-OVA). LM-OVA has a proven track record of eliciting rapid CD8 + T cell responses with long lasting memory, and is also capable of providing long lasting protection from tumor challenge [26]. Thus, the response to the same highly immunogenic antigen expressed in the context of two contrasting antigen delivery systems could be compared.…”

Section: Introductionmentioning

confidence: 99%

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Homologous Prime-Boost Vaccination with OVA Entrapped in Self-Adjuvanting Archaeosomes Induces High Numbers of OVA-Specific CD8+ T Cells that Protect Against Subcutaneous B16-OVA Melanoma

2016

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Homologous prime-boost vaccinations with live vectors typically fail to induce repeated strong CD8+ T cell responses due to the induction of anti-vector immunity, highlighting the need for alternative delivery vehicles. The unique ether lipids of archaea may be constituted into liposomes, archaeosomes, which do not induce anti-carrier responses, making them an ideal candidate for use in repeat vaccination systems. Herein, we evaluated in mice the maximum threshold of antigen-specific CD8+ T cell responses that may be induced by multiple homologous immunizations with ovalbumin (OVA) entrapped in archaeosomes derived from the ether glycerolipids of the archaeon Methanobrevibacter smithii (MS-OVA). Up to three immunizations with MS-OVA administered in optimized intervals (to allow for sufficient resting of the primed cells prior to boosting), induced a potent anti-OVA CD8+ T cell response of up to 45% of all circulating CD8+ T cells. Additional MS-OVA injections did not add any further benefit in increasing the memory of CD8+ T cell frequency. In contrast, OVA expressed by Listeria monocytogenes (LM-OVA), an intracellular bacterial vector failed to evoke a boosting effect after the second injection, resulting in significantly reduced antigen-specific CD8+ T cell frequencies. Furthermore, repeated vaccination with MS-OVA skewed the response increasingly towards an effector memory (CD62low) phenotype. Vaccinated animals were challenged with B16-OVA at late time points after vaccination (+7 months) and were afforded protection compared to control. Therefore, archaeosomes constituted a robust particulate delivery system to unravel the kinetics of CD8+ T cell response induction and memory maintenance and constitute an efficient vaccination regimen optimized for tumor protection.

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Intracellular Bacterial Vectors That Induce CD8+ T Cells with Similar Cytolytic Abilities but Disparate Memory Phenotypes Provide Contrasting Tumor Protection

Abstract: Induction of a functional CD8

Cited by 35 publications

References 47 publications

Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors

Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors

Escherichia coli Nissle 1917 Targets and Restrains Mouse B16 Melanoma and 4T1 Breast Tumors through Expression of Azurin Protein

Homologous Prime-Boost Vaccination with OVA Entrapped in Self-Adjuvanting Archaeosomes Induces High Numbers of OVA-Specific CD8+ T Cells that Protect Against Subcutaneous B16-OVA Melanoma

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