Control of immune cell entry through the tumour vasculature: a missing link in optimising melanoma immunotherapy?

Tan, Lih; Martini, Carmela; Fridlender, Zvi G.; Bonder, Claudine S.; Brown, Michael P.; Ebert, Lisa M.

doi:10.1038/cti.2017.7

Cited by 24 publications

(27 citation statements)

References 102 publications

(183 reference statements)

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“…Similarly, a higher immune score was associated with a longer survival time in melanoma and ovarian cancer, but earlier recurrence in hepatocellular carcinoma-adjacent tissue. The degree of tumour-infiltrating lymphocytes in particular activated CD8+ T-cells, within melanoma positively correlates with better prognosis ( 26 ). The decreased recruitment of tumor-infiltrating lymphocytes may lead to poor prognosis in high-risk ovarian cancer patients ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome-derived stromal and immune scores infer clinical outcomes of patients with cancer

Liu

et al. 2018

Oncol Lett

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The stromal and immune cells that form the tumor microenvironment serve a key role in the aggressiveness of tumors. Current tumor-centric interpretations of cancer transcriptome data ignore the roles of stromal and immune cells. The aim of the present study was to investigate the clinical utility of stromal and immune cells in tissue-based transcriptome data. The ‘Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data’ (ESTIMATE) algorithm was used to probe diverse cancer datasets and the fraction of stromal and immune cells in tumor tissues was scored. The association between the ESTIMATE scores and patient survival data was asessed; it was indicated that the two scores have implications for patient survival, metastasis and recurrence. Analysis of a colorectal cancer progression dataset revealed that decreased levels immune cells could serve an important role in cancer progression. The results of the present study indicated that trasncriptome-derived stromal and immune scores may be a useful indicator of cancer prognosis.

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Section: Discussionmentioning

confidence: 99%

Transcriptome-derived stromal and immune scores infer clinical outcomes of patients with cancer

Liu

et al. 2018

Oncol Lett

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“…However, using a dual tumor model we surprisingly found that synergy was achieved more effectively with anti-CTLA-4, rather than anti-PD-1. As anti-CTLA-4 promotes entry of new T cells into the tumor in addition to CD4 + and CD8 + T cell activation, whereas anti-PD-1 targets mainly rejuvenation of exhausted CD8 + T cells, [41][42][43][44] it may be possible that anti-CTLA-4 synergizes by promoting entry of the endogenous vaccine-induced T cells into the small untreated contralateral tumors, which may not have recruited or induced their own T cells. Another explanation could be that there is limited expression of PD-L1 in the untreated contralateral tumors, making blockade of the PD-1/PD-L1 axis less critical.…”

Section: Discussionmentioning

confidence: 99%

Intratumorally delivered formulation, INT230-6, containing potent anticancer agents induces protective T cell immunity and memory

Bloom

Bender²,

Tiwary

et al. 2019

OncoImmunology

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The benefits of anti-cancer agents extend beyond direct tumor killing. One aspect of cell death is the potential to release antigens that initiate adaptive immune responses. Here, a diffusion enhanced formulation, INT230-6, containing potent anti-cancer cytotoxic agents, was administered intratumorally into large (approx. 300mm 3) subcutaneous murine Colon26 tumors. Treatment resulted in regression from baseline in 100% of the tumors and complete response in up to 90%. CD8 + or CD8 + /CD4 + T cell double-depletion at treatment onset prevented complete responses, indicating a critical role of T cells in promoting complete tumor regression. Mice with complete response were protected from subcutaneous and intravenous re-challenge of Colon26 cells in a CD4 + /CD8 + dependent manner. Thus, immunological T cell memory was induced by INT230-6. Colon26 tumors express the endogenous retroviral protein gp70 containing the CD8 + T-cell AH-1 epitope. AH-1-specific CD8 + T cells were detected in peripheral blood of tumor-bearing mice and their frequency increased 14 days after treatment onset. AH-1-specific CD8 + T cells were also significantly enriched in tumors of untreated mice. These cells had an activated phenotype and highly expressed Programmed cell-death protein-1 (PD-1) but did not lead to tumor regression. CD8 + T cell tumor infiltrate also increased 11 days after treatment. INT230-6 synergized with checkpoint blockade, inducing a complete remission of the primary tumors and shrinking of untreated contralateral tumors, which demonstrates not only a local but also systemic immunological effect of the combined therapy. Similar T-cell dependent inhibition of tumor growth was also found in an orthotopic 4T1 breast cancer model.

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“…This requires cell-cell interactions via adhesion molecules such as selectin and integrin. Immune cells first undergo “rolling,” which is initiated by interactions between endothelial P/E-selectins, PNAd, and MAdCAM-1, as well as leukocyte L-selectin, PSGL-1, and E-selectin ligand 5 (Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of adhesion molecules and barrier molecules is associated with differential infiltration of immune cells in non-small cell lung cancer

Chae

Choi

Bae

et al. 2018

Sci Rep

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Immunotherapy is emerging as a promising option for lung cancer treatment. Various endothelial adhesion molecules, such as integrin and selectin, as well as various cellular barrier molecules such as desmosome and tight junctions, regulate T-cell infiltration in the tumor microenvironment. However, little is known regarding how these molecules affect immune cells in patients with lung cancer. We demonstrated for the first time that overexpression of endothelial adhesion molecules and cellular barrier molecule genes was linked to differential infiltration of particular immune cells in non-small cell lung cancer. Overexpression of endothelial adhesion molecule genes is associated with significantly lower infiltration of activated CD4 and CD8 T-cells, but higher infiltration of activated B-cells and regulatory T-cells. In contrast, overexpression of desmosome genes was correlated with significantly higher infiltration of activated CD4 and CD8 T-cells, but lower infiltration of activated B-cells and regulatory T-cells in lung adenocarcinoma. This inverse relation of immune cells aligns with previous studies of tumor-infiltrating B-cells inhibiting T-cell activation. Although overexpression of endothelial adhesion molecule or cellular barrier molecule genes alone was not predictive of overall survival in our sample, these genetic signatures may serve as biomarkers of immune exclusion, or resistance to T-cell mediated immunotherapy.

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Control of immune cell entry through the tumour vasculature: a missing link in optimising melanoma immunotherapy?

Cited by 24 publications

References 102 publications

Transcriptome-derived stromal and immune scores infer clinical outcomes of patients with cancer

Transcriptome-derived stromal and immune scores infer clinical outcomes of patients with cancer

Intratumorally delivered formulation, INT230-6, containing potent anticancer agents induces protective T cell immunity and memory

Overexpression of adhesion molecules and barrier molecules is associated with differential infiltration of immune cells in non-small cell lung cancer

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