Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy

Summary

The field of systemic cancer therapy for metastatic disease has entered an exciting era with the advent of novel immunomodulatory strategies targeting immune checkpoints. At the heart of these promising efforts are the tumour-infiltrating lymphocytes (TILs). As the reports demonstrating efficacy of modulating TIL effector function in patients with advanced stage cancer continue to accrue, it has become essential to better understand TIL immunobiology in order to further improve clinical outcome. In addition to providing an overview of the current immunotherapies available for metastatic melanoma, this review will briefly introduce the history and classification of TILs. Moreover, we will dissect the multifaceted roles of TILs in tumour-specific immunity and melanoma immune escape. The significance of TILs in melanoma prognosis and cancer immunotherapy will also be discussed, with a particular focus on their potential utility as biomarkers of patient response. The goal of personalised medicine appears to be in realistic sight, as new immunomodulatory techniques and technological innovations continue to advance the field of cancer immunotherapy. In light of recent studies highlighting the possible utility of TILs in determining therapeutic outcome, further characterisation of TIL phenotype and function has the potential to help translate individualised care into current medical practice.

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.