Melanocytic tumour pathologyTumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy
Introduction
First described by Robert Virchow in 1863, leukocytes found within tumours were initially thought to be the cells of origin of cancers arising at sites of chronic inflammation.1 Early studies appeared to suggest that these leukocytes propagated tumour growth via protumorigenic inflammatory processes.1 However, it was not long before it was recognised that these immune cells were often recruited as a defense mechanism against the tumour and that their presence frequently correlated with a favourable prognosis in patients with melanoma as well as other solid tumours, such as ovarian2 and colorectal carcinomas.3
In 1969, Wallace Clark applied the term, ‘tumour-infiltrating lymphocytes’, to refer to these immune cells deployed as part of the host response to cancer.4 In order to be regarded as TILs, lymphocytes must be in direct contact with tumour cells (RGP) and/or infiltrate tumour nests. In melanoma, Clark and Mihm reported that TILs were recruited in the radial growth phase (RGP) and led to partial regression of the primary tumour.4 Consistent with these findings, in vitro studies by Hersey demonstrated cytolytic activity of these lymphocytes against autologous tumours in melanoma patients.5 Further studies supporting the benefit of TILs revealed that their presence in the invasive vertical growth phase (VGP) of primary melanomas was associated with increased survival and decreased risk of metastasis.6, 7 Moreover, the presence of TILs in metastatic lesions appeared to also have a similar benefit. Patients with a more brisk T-cell infiltrate in lymph node metastases had improved survival rates compared with those with less reactive TIL responses.8 Consistently, adoptive transfer of autologous TILs in combination with interleukin-2 (IL-2)-based immunotherapy has resulted in tumour regression in patients with metastatic melanoma.9
Over the past several years, TILs have been identified in the primary tumour, tumour-bearing lymph nodes, and visceral metastases of numerous cancer types. Given their ubiquitous nature across a vast collection of cancers in conjunction with their anti-tumour capabilities and potential roles as prognostic indicators, which will be discussed in more detail below, TILs have been garnering much deserved attention among cancer researchers as prime targets for cancer immunotherapy. However, TILs are a heterogenous group comprised of not only effector T cells, but also of tolerogenic or T regulatory (Treg) cells, functionally exhausted T cells, natural killer (NK) cells, macrophages, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), and other immune cell types.1 Thus, better understanding of TIL phenotype and function in the context of tumour-induced and other factors within the tumour microenvironment (TME) is crucial in aiding the invention of innovative drugs and identifying the patients most likely to respond to therapy.
Section snippets
Classification of TILs in malignant melanoma
The assessment of the role of TILs in prognostication and therapy in melanoma first required the establishment of a graded system that categorises the nature and extent of TIL involvement within a tumour. In 1989, Clark and colleagues6 put forth the first comprehensive classification system defining distinct lymphocytic infiltrate patterns in melanomas (Fig. 1). They classified TILs as ‘absent’ when no lymphocytes were present or when the lymphocytes did not appose the melanoma cells.6
TILs as a predictive and prognostic biomarker
The accurate prediction of patient prognosis is paramount to selecting the appropriate therapies and improving management of melanoma patients. Evidence to support the presence of TILs as a positive prognosticator in melanoma patients has been steadily amassing. Many studies focused on both the density of TILs and their location in relation to the tumour. In a retrospective study including 669 melanoma patients, Larsen and Grude noted improved survival rates in patients with a dense lymphocytic
TIL immunobiology and melanoma immune escape
TILs comprise a heterogeneous group of lymphocytes that differ in their ability to potentiate the anti-tumour immune response. All nucleated cells express so-called major histocompatibility complex (MHC) class I proteins on their cell surface. These proteins are involved in the presentation of cytosolic antigens to T cells, including cytotoxic T lymphocytes (CTLs).27 When aberrant tumour antigens are presented on MHC class I molecules, the cancer cell expressing these non-self antigens can be
TILs and cancer immunotherapy
Cancer immunotherapy has evolved as a highly promising treatment option for patients with advanced stage melanoma.29 Accordingly, in addition to their established utility as biomarkers of melanoma prognosis,60 TILs may also serve as therapeutic targets and clinical predictors of response to immunomodulatory strategies aimed at treating metastatic disease. Melanoma immunotherapy can be broadly categorised into three groups: (1) immunisation using vaccines consisting of whole cells, immunogenic
Conclusions
In this review article, we provide an overview on the history and histological classification of TILs in human malignant melanoma. Since their discovery, multiple studies have highlighted the potential significance of TILs, not only as predictors of melanoma prognosis, but also as therapeutic targets and potential biomarkers of response to cancer immunotherapy and particularly immune checkpoint blockade. Additional insight into TIL phenotype and function, neoantigen-specific immunity, and
Acknowledgements
We apologise to those colleagues whose work could not be cited due to space limitations.
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