title: Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells.
abstract: 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.
authors.affiliation: University of Pittsburgh Cancer Institute, Hillman Cancer Center G17a, University of Pittsburgh, 5117 Centre Avenue, PA 15213, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.forename: S
authors.initials: S
authors.lastname: Goding
authors.forename: M
authors.initials: M
authors.lastname: Hagenaars
authors.forename: T
authors.initials: T
authors.lastname: Carlos
authors.forename: P
authors.initials: P
authors.lastname: Albertsson
authors.forename: P
authors.initials: P
authors.lastname: Kuppen
authors.forename: U
authors.initials: U
authors.lastname: Nannmark
authors.forename: M E
authors.initials: ME
authors.lastname: Hokland
authors.forename: P H
authors.initials: PH
authors.lastname: Basse
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018827:Carcinoma, Lewis Lung; D005109:Extracellular Matrix / Q000737:chemistry / Q000276:immunology; D005260:Female; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000098:blood supply* / Q000276:immunology* / Q000473:pathology; D016131:Lymphocyte Subsets / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D009362:Neoplasm Metastasis / Q000276:immunology* / Q000473:pathology; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology*