Activated Natural Killer Cell Tumor Retention and Cytokine Production in Colon Tumor Using a Tissue-Isolated Model

We have recently shown that adoptively transferred, IL-2-activated natural killer (A-NK) cells are able to eliminate well-established B16-F10.P1 melanoma lung metastases. However, some B16-F10.P1 lung metastases were resistant to infiltration by the A-NK cells and also resistant to the A-NK cell treatment. The infiltration-resistant (I-R) B16-F10.P1 metastases had a unique "compact" morphology compared to the "loose" morphology of the infiltration-permissive (I-P) metastases. Here, we show that I-P loose tumors and I-R compact tumors are also found in lung metastases of mouse Lewis lung carcinoma (3LL), MCA-102 sarcoma, and MC38 colon carcinoma as well as rat MADB106 mammary carcinoma origin. Furthermore, the infiltration resistance of the compact tumors is not restricted to A-NK cells, since PHA and IL-2 stimulated CD8+ T-cells (T-LAK cells) also infiltrated the compact tumors poorly. Analyses of tumors for extracellular matrix (ECM) components and PECAM-1(+) vasculature, revealed that the I-R lesions are hypovascularized and contain very little laminin, collagen and fibronectin. In contrast, the I-P loose tumors are well-vascularized and they contain high amounts of ECM components. Interestingly, the distribution pattern of ECM components in the I-P loose tumors is almost identical to that of the normal lung tissue, indicating that these tumors develop around the alveolar walls which provide the loose tumors with both a supporting tissue and a rich blood supply. In conclusion, tumor infiltration by activated NK and T cells correlates with the presence of ECM components and PECAM-1(+) vasculature in the malignant tissue. Thus, analysis of the distribution of ECM and vasculature in tumor biopsies may help select patients most likely to benefit from cellular adoptive immunotherapy.

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Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells

Yang

Goding

Hagenaars

et al. 2005

Cancer Immunol Immunother

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Comparison of in vitro antibody-targeted cytotoxicity using mouse, rat and human effectors

Bergman

Basse

Barmada

et al. 2000

Cancer Immunology, Immunotherapy

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Antibodies can direct tumor cell lysis by activating complement-mediated and cell-mediated cytoxicities (antibody-dependent cell-mediated cytotoxicity, ADCC). Clinical translation of these effects into successful cancer therapy has been slow. Choosing an appropriate animal model to test new therapeutic strategies is difficult because of species differences in immunological effector functions. In previous work, we found that an unmodified anti-ganglioside mouse IgG3 monoclonal antibody (mAb), 3F8, could successfully treat clinical tumors in humans and experimental tumors in rats but not experimental tumors in mice. We explored the reasons for this species difference by performing in vitro antibody-dependent cytotoxicity assays comparing the potency of polymorphonuclear neutrophils (PMN), natural killer (NK) cells and complement from the three species: mouse, rat and human. 3F8-dependent complement-mediated cytotoxicity produced more than 70% specific release when human and rat sera were used and only 20% with mouse serum. PMN-mediated ADCC was 35%-70% with human effectors, 25%-60% with rat and undetectable with mouse. Human eosinophils did not contribute to this ADCC. Cytotoxicity utilizing interleukin-2-activated NK cells was antibody-independent in all three species but the specific release was 60%-70% with human and rat NK cells and 10% with mouse NK cells. These data suggest that, for mouse IgG3, the rat may provide a more relevant rodent model than the mouse for testing the in vivo antitumor effects of monoclonal antibodies.

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Cells as Vehicles for Cancer Gene Therapy: The Missing Link Between Targeted Vectors and Systemic Delivery?

Harrington

Álvarez‐Vallina

Crittenden³

et al. 2002

Human Gene Therapy

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Systemic administration of currently manufactured viral stocks has not so far achieved sufficient circulating titers to allow therapeutic targeting of metastatic disease. This is due to low initial viral titers, immune inactivation, nonspecific adhesion, and loss of particles. One way to exploit the elegant molecular manipulations that have been made to increase vector targeting is to protect these vectors until they reach the local sites of tumor growth. Various cell types home preferentially to tumors and can be loaded with the constructs required to produce targeted vectors. Here we discuss the potential of using such cell carriers to chaperone precious vectors directly to the tumors. The vectors can incorporate mechanisms to achieve tumor site-inducible expression, along with tumor cell-specific expression of the therapeutic gene and/or replicating viral genomes that would be released at the tumor. In this way, the great advances that have so far been made with the engineering of vector tropisms might be genuinely exploited and converted into clinical benefit.

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Activated Natural Killer Cell Tumor Retention and Cytokine Production in Colon Tumor Using a Tissue-Isolated Model

Cited by 4 publications

References 33 publications

Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells

Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells

Comparison of in vitro antibody-targeted cytotoxicity using mouse, rat and human effectors

Cells as Vehicles for Cancer Gene Therapy: The Missing Link Between Targeted Vectors and Systemic Delivery?

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