The tumour microenvironment and implications for cancer immunotherapy

Petrulio, Christian; Kim‐Schulze, Seunghee; Kaufman, Howard L.

doi:10.1517/14712598.6.7.671

Cited by 38 publications

(20 citation statements)

References 106 publications

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“…Moreover, tumor cells themselves play a crucial role in controlling the antitumor immune response (5), allowing them to maintain their functional disorder and evade destruction by CTLs. In this regard, it has been suggested that tumor cell growth in vivo is not only influenced by CTL-tumor cell recognition (6) and tumor susceptibility to cell-mediated death, but also by the complex and highly dynamic tumor microenvironment, providing very important clues to tumor development and progression (7).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Inducible miR-210 Regulates the Susceptibility of Tumor Cells to Lysis by Cytotoxic T Cells

et al. 2012

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Hypoxia in the tumor microenvironment plays a central role in the evolution of immune escape mechanisms by tumor cells. In this study, we report the definition of miR-210 as a miRNA regulated by hypoxia in lung cancer and melanoma, documenting its involvement in blunting the susceptibility of tumor cells to lysis by antigen-specific cytotoxic T lymphocytes (CTL). miR-210 was induced in hypoxic zones of human tumor tissues. Its attenuation in hypoxic cells significantly restored susceptibility to autologous CTL-mediated lysis, independent of tumor cell recognition and CTL reactivity. A comprehensive approach using transcriptome analysis, argonaute protein immunoprecipitation, and luciferase reporter assay revealed that the genes PTPN1, HOXA1, and TP53I11 were miR-210 target genes regulated in hypoxic cells. In support of their primary importance in mediating the immunosuppressive effects of miR-210, coordinate silencing of PTPN1, HOXA1, and TP53I11 dramatically decreased tumor cell susceptibility to CTL-mediated lysis. Our findings show how miR-210 induction links hypoxia to immune escape from CTL-mediated lysis, by providing a mechanistic understanding of how this miRNA mediates immunosuppression in oxygen-deprived regions of tumors where cancer stem-like cells and metastatic cellular behaviors are known to evolve. Cancer Res; 72(18); 4629-41. Ó2012 AACR.

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Section: Introductionmentioning

confidence: 99%

Hypoxia-Inducible miR-210 Regulates the Susceptibility of Tumor Cells to Lysis by Cytotoxic T Cells

et al. 2012

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“…6 In addition, the tumor microenvironment has to be conducive to immune cell function. 7 In normal immune responses to microorganisms, appropriate signals (danger signals) are produced that result in the localized production of chemokines and cytokines. 8 Instrumental in this process are resident dendritic cells (DC) that respond to ligation of Toll-like receptors (TLR) by pathogen-associated molecular patterns present on microbial products.…”

Section: Introductionmentioning

confidence: 99%

Tumor-specific dendritic cells generated by genetic redirection of Toll-like receptor signaling against the tumor-associated antigen, erbB2

Darcy

Kershaw

2007

Cancer Gene Ther

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Dendritic cells (DC) perform an important role in the initiation of the immune response through the local secretion of inflammatory mediators within diseased tissue in response to Toll-like receptor (TLR) ligation. However, DC vaccine strategies fail to make use of this capability against cancer. To harness the TLR response capability of DC against cancer, we tested a series of recombinant genes for their ability to redirect DC function specifically against a tumor-associated antigen. Each gene encoded a cell surface chimeric protein made up of extracellular single-chain immunoglobulin anti-erbB2 linked to an intracellular TLR-signaling component composed of either myeloid differentiation factor 88, interleukin-1 receptor-associated kinase-1 (IRAK-1) or the cytoplasmic domain of TLR4. Each gene was expressed in the DC line, JAWS II, to a similar degree following retroviral transduction. However, only the chimera containing IRAK-1 was able to mediate interleukin-12 and tumor necrosis factor-a secretion. Since TLR engagement can also activate DC and enhance their ability to stimulate T cells, we ligated the chimeric anti-erbB2-IRAK-1 receptor and determined the effect on the stimulation of T cells. We found that JAWS II cells triggered through chimeric anti-erbB2-IRAK-1 displayed an enhanced ability to stimulate ovalbumin-specific OT-II CD4 þ T cells. This first description of the generation of tumorreactive DC may lead to the development of new cell-based vaccines that can act at both the tumor site to induce danger and at the lymph node to stimulate a specific T-cell response.

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“…[5][6][7][8] During cancer progression, cancer cell interactions with the ECM are crucial for tumor growth, metastasis and responses to antitumor therapy. 5,9 Moreover, angiogenesis plays a critical role in tumor growth. 10,11 Thus, the stroma tightly controls cancer cell behavior.…”

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confidence: 99%

Host stromal versican is essential for cancer‐associated fibroblast function to inhibit cancer growth

Fanhchaksai

Okada

Nagai

et al. 2015

Intl Journal of Cancer

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The stroma provides a microenvironment that regulates tumor cell behavior. The extracellular matrix (ECM) has long been recognized to be important in tumor cell behavior, and previous studies have revealed the impact of individual matrix molecules on tumor progression. Although several reports have highlighted some central roles of tumor cell-expressed versican, the role of host stromal versican is not yet understood. In this study, we demonstrate that versican is an important molecule in the functional ECM structure and maintaining cancer-associated fibroblasts, using versican-negative QRsP11 fibrosarcoma cells. By their subcutaneous injection with cre-expressing adenoviruses to versican-floxed mice, we demonstrate that loss of host stromal versican facilitates tumor cell proliferation, and following angiogenesis, decreases cancer-associated fibroblasts, diminishes collagen fibers and alters hyaluronan distribution, concomitant with upregulation of hyaluronan, TGFb and VEGFmediated signaling. When the versican V3 variant consisting of G1 and G3 domains was expressed in tumor cells, it was integrated into the ECM, regained collagen fibers and cancer-associated fibroblasts and resulted in successful recovery of tumor growth inhibition, indicating that whatever cells produce, the G1 and G3 domains are adequate for versican function. Collectively, our results indicate a dynamic function of versican in the ECM that regulates tumor cell behavior. A greater understanding of the regulation of versican expression may contribute to the development of cancer therapies.Cancer cell behavior is largely affected by its microenvironment (such as the stroma), which comprises the extracellular matrix (ECM), fibroblasts and blood vessels.

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The tumour microenvironment and implications for cancer immunotherapy

Cited by 38 publications

References 106 publications

Hypoxia-Inducible miR-210 Regulates the Susceptibility of Tumor Cells to Lysis by Cytotoxic T Cells

Hypoxia-Inducible miR-210 Regulates the Susceptibility of Tumor Cells to Lysis by Cytotoxic T Cells

Tumor-specific dendritic cells generated by genetic redirection of Toll-like receptor signaling against the tumor-associated antigen, erbB2

Host stromal versican is essential for cancer‐associated fibroblast function to inhibit cancer growth

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