Immunotherapy: target the stroma to hit the tumor

Kammertoens, Thomas; Schüler, Thomas; Blankenstein, Thomas

doi:10.1016/j.molmed.2005.03.002

Cited by 83 publications

(52 citation statements)

References 60 publications

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“…Furthermore, in line with our simulations, it has been shown that tumors can use the stroma to mitigate the immune response (53). Regarding immunotherapy, it has been suggested that immune response against a tumor is more efficient if the immune cells also destroy the stroma (48). Our model provides a simple explanation for this behavior.…”

Section: Discussionsupporting

confidence: 84%

“…Currently, several experimental therapies in the clinic aim to target the stroma. Indeed, most prominent are approaches with enzymes that aim to enhance the permeability of stroma (4,5,48). Our data show that these approaches can be very effective but can also have adverse effects that need to be considered before clinical development of new substances.…”

Section: Discussionmentioning

confidence: 92%

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In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

et al. 2017

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Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n ¼ 20) including tumor cells, lymphocytes, stroma, and necrosis to generate a multiagent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n ¼ 37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyteenriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n ¼ 261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, P ¼ 0.0219) as compared with high stroma and high lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in preestablished tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico. These results can help guide the rational design of complex therapeutic interventions, which target the colorectal cancer microenvironment.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 92%

In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

et al. 2017

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“…Because there was a weak but significant effect in nude mice, it is possible that this response is provided by direct activation of the tumor stroma (56) or even activation of TLRs on tumor cells themselves (13,57), although the role of the latter in tumor biology is still unclear (14,58). Regardless of the specific mechanism involved in our study, it is clear that a greater understanding of the actions of the TLR system within the complex environment of a tumor is needed to fully harness its therapeutic potential.…”

Section: Tumor Resolution and Type I Ifnmentioning

confidence: 99%

Targeting the Effector Site with IFN-αβ-Inducing TLR Ligands Reactivates Tumor-Resident CD8 T Cell Responses to Eradicate Established Solid Tumors

Currie

Most

Broomfield

et al. 2008

The Journal of Immunology

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Effective antitumor CD8 T cell responses may be activated by directly targeting the innate immune system within tumors. We investigated this response by injecting a range of TLR agonists into established tumors using a mouse model of malignant mesothelioma stably transduced with the hemagglutinin (HA) gene as a marker Ag (AB1-HA). Persistent delivery of the dsRNA mimetic poly(I:C) into established AB1-HA tumors resulted in complete tumor resolution in 40% of mice, with the remaining mice also showing a significant delay in tumor progression. Experiments in athymic nude mice along with CD8 depletion and IFN-αβ blocking studies revealed that tumor resolution required both CD8 T cells and type I IFN induction, and was associated with local changes in MHC class I expression. Surprisingly, however, tumor resolution was not associated with systemic dissemination or tumor infiltration of effector CD8 T cells. Instead, the antitumor response was critically dependent on the reactivation of tumor-resident CD8 T cell responses. These studies suggest that, once reactivated, pre-existing local CD8 T cell responses are sufficient to resolve established tumors and that in situ type I IFN is a determining factor.

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“…Esses avanços, na maior parte dos casos, devem-seà melhor compreensão do câncer no ponto de vista genético e molecular. Uma vez estabelecida a doença e sabendo que as interações da região afetada podem ser estudadas em nível molecular, celular ou tecidual [3,6]é possível propor uma abordagem matemática com uso de diversos modelos dependendo do tipo de interação e do nível que quer ser estudado [9] sendo que os focos de estudo estipulam abordagens que, entre muitos outros, vão desde uma interação de competição [7] até uma modelagem hospedeiro-parasita como variante de uma interação presa-predador com encontros aleatórios fazendo uso de duas ou mais equações diferenciais ordinárias [10][11][12]15].…”

Section: Introductionunclassified

Análise da Estabilidade de um Problema em Imuno-oncologia: uma Abordagem Teórica Ampliada

Palomino

2018

Tend. Mat. Apl. Comput.

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Recebido em 12 dezembro, 2016 / Aceito em 15 maio, 2017 RESUMO. O cânceré uma questão de prioridade pública que aflige o mundo e muitos esforços através da pesquisa científica estão sendo realizados para o seu combate. Nesse sentido, a imunoterapia, como tratamento em imuno-oncologia,é considerada como modalidade terapeûtica praticada nas duasúltimas décadas. Neste trabalho, estuda-se o crescimento das células tumorais levando em consideração o microambiente determinado pela interação que há entre as células tumorais com as células efetoras, citocinas anti-inflamatórias e um fator imuno-supressivo. Apresentam-se duas variantes dos modelos matemáticos de [1] com a inserção de um termo switching [11,12,15] nesses modelos. Faz-se o estudo qualitativo dos modelos e com a análise de estabilidade e as simulações numéricas dos mesmos ilustram-se de uma forma ampliada os resultados desta pesquisa.Palavras-chave: modelagem matemática, imuno-oncologia, imunoterapia, existência e unicidade, análise de estabilidade. INTRODUÇÃOO cânceré uma doença que, naúltima década, tem dado muita preocupação nos governos, sendo uma questão prioritária na saúde pública. A Agência Internacional para pesquisa em câncer da OMS -Organização Mundial da Saúde, estimou que houve 14,2 milhões de casos novos e 8,2 milhões de mortes anuais no mundo todo em 2012. Estimou-se que em 2015 esse número chegou a 9 milhões de casos novos e 13,2 milhões de mortes e para o ano 2025 o número de casos novos chegará a 20 milhões. Nos Estados Unidos, as estatísticas apontam que 1600 pessoas morrem por dia por causa do câncer (representou 23% do total de mortes em 2010) e na Europa esses números não são muito diferentes. Dados fornecidos pelo Instituto Nacional do Câncer -INCA apontam que no Brasil, em 2016, se estima a ocorrência de 595 mil casos novos da doença (quase 300 mil casos do sexo feminino contra 295 mil do masculino). O câncer de próstataé o de maior incidência no sexo masculino (28,6% das neoplasias em homens) e no sexo femininoé o câncer de mama (28,1% das neoplasias em mulheres) [4]. * Trabalho apresentado no XXXVI CNMAC.

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Immunotherapy: target the stroma to hit the tumor

Cited by 83 publications

References 60 publications

In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

Targeting the Effector Site with IFN-αβ-Inducing TLR Ligands Reactivates Tumor-Resident CD8 T Cell Responses to Eradicate Established Solid Tumors

Análise da Estabilidade de um Problema em Imuno-oncologia: uma Abordagem Teórica Ampliada

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