Abstract
Established cancers are frequently associated with a lymphocytic infiltrate that fails to clear the tumour mass. In contrast, the importance of recruited lymphocytes during premalignancy is less well understood. In a mouse model of premalignant skin epithelium, transgenic mice that express the human papillomavirus type 16 (HPV16) E7 oncoprotein under a keratin 14 promoter (K14E7 mice) display epidermal hyperplasia and have a predominant infiltrate of lymphocytes consisting of both CD4 and CD8 T cells. Activated, but not naïve T cells, were shown to preferentially traffic to hyperplastic skin with an increased frequency of proliferative CD8+ T cells and CD4+ T cells expressing CCR6 within the tissue. Disruption of the interaction between E7 protein and retinoblastoma tumour suppressor protein (pRb) led to reduced epithelial hyperplasia and T cell infiltrate. Finally, while K14E7 donor skin grafts are readily accepted onto syngeneic, non-transgenic recipients, these same skin grafts lacking skin-resident lymphocytes were rejected. Our data suggests that expression of a single oncoprotein in the epidermis is sufficient for lymphocyte trafficking (including immunosuppressive lymphocytes) to premalignant skin.
Highlights
The initiation of tumours requires genetic and epigenetic alterations to cell cycle control and the generation of a supportive, extrinsic microenvironment
Mice K14E7 mice [10], in which the HPV16E7 protein is driven from a keratin 14 promoter on a C57BL/6 background, C57BL/ 6, B6.SJL-Ptprc (CD45.1) and RAG12/2 mice were obtained from the Animal Resource Centre (Perth, Australia) and the Princess Alexandra Hospital Biological Research Facility (PAHBRF) (Brisbane, Australia)
To address the tissue distribution of E7-specific lymphocytes in K14E7 mice, we tracked the fate of CD45.1+CD8+ E7TCR-b chain transgenic cells transferred into CD45.2+ K14E7 mice
Summary
The initiation of tumours requires genetic and epigenetic alterations to cell cycle control and the generation of a supportive, extrinsic microenvironment. While reports of inflammation in cancer have generally focused on the activity of innate immune cells, the presence of infiltrating lymphocytes has been recognised in advanced solid tumours [4]. One view suggests that constant immune pressure drives the evolution of tumours towards immune escape and this has been elegantly described in the cancer immunoediting model [5]. Within this framework, cancer cells exist in an equilibrium state with the immune system for many years before eventually gaining attributes which negate the immune response. One strategy for obtaining the equilibrium state in the tumour microenvironment would be the recruitment of immunosuppressive lymphocyte subsets such as regulatory T cells. A key question is whether premalignant lesions recruit a suppressive lymphocyte infiltrate to facilitate the equilibrium phase of tumour development
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