Use of tumour-responsive T cells as cancer treatment

Summary

The stimulation of a tumour-specific T-cell response has several theoretical advantages over other forms of cancer treatment. First, T cells can home in to antigen-expressing tumour deposits no matter where they are located in the body—even in deep tissue beds. Additionally, T cells can continue to proliferate in response to immunogenic proteins expressed in cancer until all the tumour cells are eradicated. Finally, immunological memory can be generated, allowing for eradication of antigen-bearing tumours if they reoccur. We will highlight two direct methods of stimulating tumour-specific T-cell immunity: active immunisation with cancer vaccines and infusion of competent T cells via adoptive T-cell treatment. Preclinical and clinical studies have shown that modulation of the tumour microenvironment to support the immune response is as important as stimulation of the most appropriate effector T cells. The future of T-cell immunity stimulation to treat cancer will need combination approaches focused on both the tumour and the T cell.

Introduction

T lymphocytes can be found infiltrating human tumours and have been associated with both an improved or poor prognosis. Investigations suggest that this contradiction can be explained by close analysis of the phenotype of the tumour-infiltrating T lymphocyte. T cells can be broadly classified as cytotoxic CD8+ T cells, which can directly kill an antigen-expressing cell or cytokine-secreting CD4+ T cells. The CD4+ T-cell response can elicit both immune stimulatory or immune inhibitory effects. Specific CD4+ T-helper (Th) cell phenotypes are crucial for the expansion and persistence of tissue-destructive CD8+ T cells. Th1 CD4+ T cells secrete type I cytokines such as interferon (IFN) γ, resulting in the activation of antigen-presenting cells, which stimulate a CD8+ T-cell response.¹ Th2 CD4+ T-cells secrete type II cytokines, such as interleukin 4 (IL4), in response to antigen. Th2 CD4+ T cells can limit the activation of antigen-presenting cells and enhance humoral immunity as well as the influx of innate immune cells such as eosinophils and granulocytes.² The newly identified Th17 CD4+ T cell secretes IL17, eliciting tissue inflammation implicated in autoimmunity.³ Finally, CD4+FOXP3+ T regulatory (Treg) cells will inhibit the development of an adaptive T-cell response directed against self-molecules, especially self-tumour antigens, via secretion of immunosuppressive cytokines such as IL10 or direct inhibition of antigen-presenting cells.⁴

The interplay of specific T-cell phenotypes is highlighted in an analysis⁵ of more than 400 colon cancers for tumour-infiltrating lymphocytes (TIL). With tissue microarrays, investigators showed that a high density of CD8+ effector memory T cells in the tumour parenchyma was associated with increased survival. In a more detailed study of gene-expression patterns in a subset of tumours from 75 of the patients with colon cancer,⁶ data suggested that an upregulation of genes related to Th1 adaptive immune response was associated with a decreased risk of relapse.⁶

Conversely, the presence of Treg cells seems to correlate with a poor prognosis in several tumour types in large population-based studies. After assessing tumours in more than 300 patients with hepatocellular carcinoma, investigators showed both improved disease-free and overall survival in patients whose tumours had low numbers of Treg cells and high numbers of activated CD8+ T cells, measured by granzyme B staining, compared with patients whose tumours had high numbers of Treg cells and low numbers of activated CD8+ T cells.⁷ Intratumoural Treg cells were assessed by immunohistochemical staining in more than 200 patients with invasive breast cancer.⁸ Individuals with high numbers of Treg cells in their tumours had a shorter relapse-free and overall survival than did those with low Treg-cell infiltrate. These population-based analyses, using large numbers of well-defined cases, provide new insight into the role of T cells in cancer progression.

Direct evidence that tumour-specific T cells can induce an antitumour response is shown by the infusion of T cells used to treat patients with cancer. Donor lymphocyte infusions, used once patients with haematological malignant diseases have relapsed after allogeneic transplantation, have become a standard of care resulting in durable complete remissions in many individuals.9, 10 The clinical response is presumably due to a graft-versus-tumour effect.¹¹ Infusion of tumour-specific T cells in solid tumours has also met with some success. Transfer of autologous T cells derived from TIL resulted in a 51% response in 35 treated patients with refractory metastatic melanoma.¹² Although responses were not durable, evidence of substantial immunological remodelling of the tumour was seen, resulting in immune escape.

Unfortunately, tumours possess many mechanisms to escape immune recognition. Most defined cancer-associated immunogenic proteins, or tumour antigens, are non-mutated self-proteins; thus, systemic tolerance is a major mechanism of tumour immune escape. As described, Treg cells limit inflammation and prevent autoimmunity and are important in inhibiting self-antitumour immune responses. Other forms of peripheral tolerance include deletion, ignorance, and anergy. Deletion in the periphery is similar to central deletion, in which a cell expressing a T-cell receptor with high affinity for a self-antigen is deleted. When self-reactive T cells encounter self-antigen, the T cells can upregulate the death receptor Fas, resulting in T-cell apoptosis.¹³ Ignorance is thought to occur when self-reactive T cells persist but are not activated by the antigen. T cells can also remain ignorant of an antigen if the antigen is not easily accessible to the peripheral blood or lymphatic system.¹⁴ Anergy is a state of unresponsiveness, and is traditionally thought to occur when T-cell-receptor ligation happens in the absence of costimulation.¹⁵ Immune receptor and costimulatory molecules have often been downregulated or lost in tumour cells.¹⁶

Tumours directly produce a local suppressive milieu that affects the activity of the infiltrating immune cells. For instance, tumours can downregulate various factors in antigen processing (eg, MHC molecules).¹⁷ Furthermore, tumours can secrete inhibitory cytokines, such as IL10 and transforming growth factor (TGF) β, which can aid recruitment of Treg cells and inhibition of dendritic-cell maturation.¹⁸ Many tumours also express ligands that can interact with infiltrating T cells to provide negative stimulation, which inhibits or reduces the effector functions of specific cytotoxic T lymphocytes.19, 20 The tumour stroma can also limit the therapeutic efficacy of activated T cells by acting as a physical barrier as well as by elaborating cytokines and other soluble factors that promote cell growth and remodelling.²¹ Immune-based treatments will probably be most effective at low or non-detectable levels of tumour burden.