T Lymphocytes Restrain Spontaneous Metastases in Permanent Dormancy

Romero, Irene Gallego; Garrido, Cristina; Algarra, Ignacio; Collado, Antonia; Garrido, Federico; García-Lora, Angel

doi:10.1158/0008-5472.can-13-2084

Cited by 54 publications

(65 citation statements)

References 46 publications

(53 reference statements)

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“…Sustaining such host-protective immune responses by booster immunization or novel strategies that could give rise to memory cells is feasible and safe. It has been shown that T cells can prevent spontaneous tumor metastasis by maintaining malignant cells in permanent dormancy (22). In a murine model of B-cell lymphoma, Farrar and colleagues reported that IFN-g-producing CD8…”

Section: Immunotherapy Is a Promising Approach For Tumor Dormancy Andmentioning

confidence: 99%

The Inherent Premise of Immunotherapy for Cancer Dormancy

Manjili

2014

Cancer Research

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Clinical cancer dormancy is evident from the detection of circulating tumor cells in the blood and tissueresiding disseminated tumor cells in the bone marrow of cancer survivors who have been clinically disease free. Emerging evidence from clinical and preclinical studies suggests that tumor dormancy is a critical step in the development of both primary cancer and advanced-stage disease. In this review, it is shown that (i) naturally occurring tumor dormancy precedes occurrence of primary cancer, and (ii) conventional cancer therapies result in treatment-induced tumor dormancy, which in turn could lead to distant recurrence of cancer or permanent tumor dormancy, depending on immunogenic status of dormancy. Given that cellular dormancy is an evolutionary conserved survival mechanism in biologic systems, any stress or cytotoxic therapy could trigger cellular dormancy. Therefore, a successful cancer therapy is likely to be achieved by establishing permanent tumor dormancy and preventing distant recurrence of cancer or by eliminating dormant tumor cells. This could be accomplished by cancer immunotherapy because of the establishment of long-term memory responses. Cancer Res; 74(23); 6745-9. Ó2014 AACR.

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Section: Immunotherapy Is a Promising Approach For Tumor Dormancy Andmentioning

confidence: 99%

The Inherent Premise of Immunotherapy for Cancer Dormancy

Manjili

2014

Cancer Research

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“…The original cancer murine model comprises different clone cell lines derived from a methylcholanthrene-induced fibrosarcoma and cell lines derived from the spontaneous metastases obtained with each of these clones (41). We found an elevated spontaneous metastatic capacity in tumor clones that were highly positive for MHC-I and no metastatic capacity in MHC-Inegative clones and mice with the latter remained metastasisfree throughout their life (10,42). We expected MHC-I-negative GR9-B11 tumor cell clone to lack migratory and invasive capacities, but when we repeated the same spontaneous metastasis assays in immunodeficient mice, a large number of overt pulmonary metastases appeared in all of the animals (10).…”

Section: A Novel Preclinical Model Of Permanent Immunemediated Metastmentioning

confidence: 95%

“…It took our group more than two decades of research using a cancer murine model of spontaneous metastases to study the characteristics and mechanisms of the metastatic process. We recently reported a novel preclinical cancer model of permanent immune-mediated metastatic dormancy (10). The original cancer murine model comprises different clone cell lines derived from a methylcholanthrene-induced fibrosarcoma and cell lines derived from the spontaneous metastases obtained with each of these clones (41).…”

Section: A Novel Preclinical Model Of Permanent Immunemediated Metastmentioning

confidence: 99%

“…Hence, the tumor cells were able to migrate and invade in the absence of a T lymphocyte-mediated immune response. The immune response was analyzed in tumor-bearing immunocompetent mice, detecting an increase in T lymphocytes, dendritic cells, and macrophages (10). We then investigated whether this immune response destroyed DTCs or merely kept them in a state of dormancy.…”

Section: A Novel Preclinical Model Of Permanent Immunemediated Metastmentioning

confidence: 99%

“…Both propositions have been supported by experimental data found in human and animal cancers. Thus, disseminated metastatic cells have also been found to remain in permanent dormancy throughout the life of animals, and autopsies of humans have detected small tumors or metastatic nodules that had remained in dormancy (9,10). Hence, dormancy is a well-documented stage in cancer progression, during which cancer cells are controlled and maintained in a latent state.…”

Section: Introductionmentioning

confidence: 99%

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Metastases in Immune-Mediated Dormancy: A New Opportunity for Targeting Cancer

2014

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The aim of any anticancer treatment is to avoid, control, or eliminate disseminated tumor cells. Clinical and experimental evidence has revealed that metastases can remain in a latency state, that is, metastasis dormancy. Three mechanisms are thought to be involved in cancer dormancy: cellular dormancy, angiogenic dormancy, and immune-mediated dormancy. Here, we review the mechanisms and cells involved in immune-mediated cancer dormancy and discuss current and future immunotherapeutic strategies.

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Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype

Garrido

Romero

Aptsiauri

et al. 2014

Intl Journal of Cancer

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Intratumor heterogeneity among cancer cells is promoted by reversible or irreversible genetic alterations and by different microenvironmental factors. There is considerable experimental evidence of the presence of a variety of malignant cell clones with a wide diversity of major histocompatibility class I (MHC-I) expression during early stages of tumor development. This variety of MHC-I phenotypes may define the evolution of a particular tumor. Loss of MHC-I molecules frequently results in immune escape of MHC-negative or -deficient tumor cells from the host T cell-mediated immune response. We review here the results obtained by our group and other researchers in animal models and humans, showing how MHC-I intratumor heterogeneity may affect local oncogenicity and metastatic progression. In particular, we summarize the data obtained in an experimental mouse cancer model of a methylcholanthrene-induced fibrosarcoma (GR9), in which isolated clones with different MHC-I expression patterns demonstrated distinct local tumor growth rates and metastatic capacities. The observed "explosion of diversity" of MHC-I phenotypes in primary tumor clones and the molecular mechanism ("hard"/irreversible or "soft"/reversible) responsible for a given MHC-I alteration might determine not only the metastatic capacity of the cells but also their response to immunotherapy. We also illustrate the generation of further MHC heterogeneity during metastatic colonization and discuss different strategies to favor tumor rejection by counteracting MHC-I loss. Finally, we highlight the role of MHC-I genes in tumor dormancy and cell cycle control.Phenotypic and functional heterogeneity among cancer cells in the same tumor, a consequence of genetic or epigenetic alterations, influences the biological behavior of tumor cell clones and their interaction with the immune system. 1,2 It would be useful to identify key factors and biomarkers for metastatic progression and for predicting the outcome of therapeutic intervention.3,4 One of these factors is tumor MHC-I expression, which is associated with T/NK-cell mediated antitumor immunity and plays an important role in the interaction between the expression of tumor suppression genes and cancer immunogenicity.5-9 MHC-I loss has been reported in up to 90% of certain types of human cancers and is a mechanism widely used by tumor cells to evade T cell-mediated recognition and destruction. 10,11 The molecular alterations underlying MHC-I loss can be divided between reversible ("soft") and irreversible structural ("hard") defects, both of which have been described in solid tumors, cancer cell lines, and metastatic lesions. The likelihood of inducing tumor rejection by the recovery of MHC-I antigens appears to be strongly influenced by the soft or hard nature of the molecular defect. 12-15The frequency and molecular mechanisms of MHC-I loss have been amply studied in various types of malignancy over recent years. Nevertheless, it has not been fully elucidated how MHC-I loss variants are generated in the prim...

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T Lymphocytes Restrain Spontaneous Metastases in Permanent Dormancy

Cited by 54 publications

References 46 publications

The Inherent Premise of Immunotherapy for Cancer Dormancy

The Inherent Premise of Immunotherapy for Cancer Dormancy

Metastases in Immune-Mediated Dormancy: A New Opportunity for Targeting Cancer

Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype

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