Targeting the Primary Tumor to Generate CTL for the Effective Eradication of Spontaneous Metastases

Yü, Ping; Lee, Youjin; Wang, Yang; Liu, Xiaojuan; Auh, Sogyong; Gajewski, Thomas F.; Schreiber, Hans; You, Zhaoyang; Kaynor, Campbell; Wang, Xinzhong; Fu, Yang Xin

doi:10.4049/jimmunol.179.3.1960

Cited by 72 publications

(82 citation statements)

References 31 publications

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“…Using a xenograft tumor model in which human breast cancer cells were inoculated to athymic nude mice, LIGHT directly inhibited tumor growth by causing apoptosis in the absence of T cells [68]. We have shown in multiple tumor models that LIGHT mediated tumor regression is dependent on T cells, especially CD8 + T cells [40,69]. However, our results do not exclude the possibility that the induction of apoptosis of tumor cells by LIGHT also causes increased release of tumor antigen, leading to enhanced priming and T cell-dependent antitumor immunity.…”

Section: Tumor Cell Apoptosis Induced By Light Promotes Immune Recognmentioning

confidence: 99%

“…The advantages of the adenoviral delivery system are 1) high production of nonreplicable virus; 2) activation of innate immunity; 3) an ability to express its carrying gene in non-dividing cells, and 4) ease of expression in most tumor cell lines. Administration of Ad-LIGHT into the tumor tissue leads to the complete rejection of an aggressive fibrosacoma Ag104L d and retards the growth of other tumors, such as melanoma B16, colon cancer MC38, and breast cancer 4T1 in mice [69]. The poorly immunogenic 4T1 mammary carcinoma closely mimics human breast cancer in its anatomical site, immunogenicity, growth characteristics, and more importantly, metastatic properties [97][98][99].…”

Section: Generation Of Ctl In the Light-mediated Tumor Environment --mentioning

confidence: 99%

“…We have demonstrated in this model that generating immune responses in primary tumor tissues prior to surgical resection can produce tumor-specific effector T cells sufficient to eradicate distant metastases in a CD8-dependent fashion. Local treatment with Ad-LIGHT initiated priming of tumor-specific CD8 + T cells directly in the primary tumor, with subsequent exit of CTLs which homed to distal tumors to elicit immune-mediated eradication of spontaneous metastases [69]. Recent study has also shown that attenuated Salmonella engineered to produce LIGHT inhibit primary tumor growth as well as dissemination of pulmonary metastases [100].…”

Section: Generation Of Ctl In the Light-mediated Tumor Environment --mentioning

confidence: 99%

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Targeting tumors with LIGHT to generate metastasis-clearing immunity

Yü¹,

Fu²

2008

Cytokine & Growth Factor Reviews

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Metastastic diseases cause the majority of morbidity and mortality of cancer patients. Established tumors form both physical and immunological barriers to limit immune detection and destruction. Current immunotherapy of vaccination and adoptive transfer shows limited effect at least in part due to the existing barriers in the tumors and depending on the knowledge of tumor antigens. Tumor necrosis factor superfamily member 14 (TNFSF14) LIGHT interacts with stromal cells, dendritic cells, NK cells, naïve and activated T cells and tumor cells inside the tumor tissues via its two functional receptors, HVEM and lymphotoxin β receptor (LTβR). Targeting tumor tissues with LIGHT leads to augmentation of priming, recruitment, and retention of effector cells at tumor sites, directly or indirectly, to induce strong anti-tumor immunity to inhibit the growth of primary tumors as well as eradicate metastases. Intratumor treatment would break tumor barriers and allow strong immunity against various tumors without defining tumor antigens. This review summarizes recent findings to support that LIGHT is a promising candidate for an effective cancer immunotherapy.

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Section: Tumor Cell Apoptosis Induced By Light Promotes Immune Recognmentioning

confidence: 99%

Section: Generation Of Ctl In the Light-mediated Tumor Environment --mentioning

confidence: 99%

Section: Generation Of Ctl In the Light-mediated Tumor Environment --mentioning

confidence: 99%

See 1 more Smart Citation

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Yü¹,

Fu²

2008

Cytokine & Growth Factor Reviews

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“…LIGHT is predominantly expressed on immune cells, especially on the surface of immature Dendritic Cells (DCs) and activated T cells. Forced expression of LIGHT in tumor cells promotes the formation of lymphoid-like structures for direct T-cell sequestration and activation, leading to tumor regression (Yu et al, 2004;Yu et al, 2007). Furthermore, adoptive transfer of LIGHT-expressing mesenchymal stem cells can enhance T cell infiltration and efficiently control tumors (Zou et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

Tang¹,

Wang²,

Chlewicki³

et al. 2016

Cancer Cell

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149

140

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SUMMARYImmune checkpoint blockade therapies fail to induce responses in majority of cancer patients; so how to increase the objective response rate becomes an urgent challenge. Here we demonstrate that sufficient T cell infiltration in tumor tissues is a prerequisite for response to PD-L1 blockade. Targeting tumors with tumor necrosis factor superfamily member LIGHT activates lymphotoxin beta receptor signaling, leading to the production of chemokines that recruit massive numbers of T cells. Furthermore, targeting non-T cell-inflamed tumor tissues by antibody-guided LIGHT creates a T cell-inflamed microenvironment and overcomes tumor resistance to checkpoint blockade. Our data indicates that targeting LIGHT might be a potent strategy to increase the responses to checkpoint blockades and other immunotherapies in non-T cell-inflamed tumors.

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“…Administration of Ad-LIGHT into the tumor tissue leads to the complete rejection or significant delay of aggressive murine tumors. 75 Local treatment with Ad-LIGHT initiated priming of tumor-specific CD8 1 T cells directly in the primary tumor, with subsequent exit of CTLs which homed to distal tumors to elicit immune-mediated eradication of spontaneous metastases. 75 This strategy is an example that the generation of immune responses in primary tumor tissues prior to surgical resection can produce tumor-specific effector T cells sufficient to eradicate distant metastases in a CD8-dependent fashion.…”

Section: Targeted Immunotherapy To Primary Tumor Tissues Can Generatementioning

confidence: 99%

Targeting and utilizing primary tumors as live vaccines: changing strategies

Yang

Mortenson

2011

Cell Mol Immunol

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Tumor metastases and relapse are the major causes of morbidity and mortality in cancer. Although surgery, chemotherapy and/or radiation therapy can typically control primary tumor growth, metastatic and relapsing tumors are often inaccessible or resistant to these treatments. An adaptive immune response can be generated during these conventional treatments of the primary tumor, and presumably both the primary tumor and secondary metastases share many of the same or similar antigenic characteristics recognized by the immune system. Thus, when established, this response should be able to control metastatic growth and tumor relapse. This review summarizes the mechanisms by which antitumor immune responses are generated, and recent findings supporting the hypothesis that many therapies targeting primary tumors can generate antitumor adaptive immune responses to prevent metastases and tumor relapse. Keywords: chemotherapy; immunotherapy; metastasis; radiotherapy; tumor vaccine INTRODUCTION Conventional treatments such as surgery and chemotherapy are effective means of eliminating or reducing primary tumor growth, but have not proved effective in eradicating metastases. Because metastatic disease may not respond similarly to chemotherapies used in treating the primary tumor, 1 recent research has focused on the importance of generating an antitumor immune response to control metastatic disease. Presumably, both the primary tumor and secondary metastases share many of the same or similar antigenic characteristics recognized by the immune system; yet, there has been no clear strategy formulated in which a patient's own tumor tissues is used to generate an antitumor adaptive immune response for the eradication of metastases and prevention of relapse. Once tumors metastasize, curing the disease is difficult and rare. This review summarizes recent findings supporting the hypothesis that targeting primary tumors with both conventional and new therapies can potentially generate antitumor adaptive immune responses that prevent metastases and relapse.Due to the vast number of genetic changes associated with carcinogenesis, tumors express many neo-antigens and mutated antigens. Indeed, much evidence exists to indicate that many cancers are antigenic and thus recognizable by the adaptive immune system. 2 Mere recognition by adaptive immunity, however, is insufficient, given that these antigenic cancers rarely regress spontaneously. Effective antitumor immunity depends on both the presence of tumor-reactive lymphocyte precursors and means by which these precursor lymphocytes can be activated. Most T cells with high affinity to tissue-specific antigens are deleted in the thymus or later tolerized in the peripheral

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Targeting the Primary Tumor to Generate CTL for the Effective Eradication of Spontaneous Metastases

Cited by 72 publications

References 31 publications

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Targeting tumors with LIGHT to generate metastasis-clearing immunity

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

Targeting and utilizing primary tumors as live vaccines: changing strategies

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