Investigating T Cell Immunity in Cancer: Achievements and Prospects

Abstract

T cells play a key role in tumour surveillance, both identifying and eliminating transformed cells. However, as tumours become established they form their own suppressive microenvironments capable of shutting down T cell function, and allowing tumours to persist and grow. To further understand the tumour microenvironment, including the interplay between different immune cells and their role in anti-tumour immune responses, a number of studies from mouse models to clinical trials have been performed. In this review, we examine mechanisms utilized by tumour cells to reduce their visibility to CD8⁺ Cytotoxic T lymphocytes (CTL), as well as therapeutic strategies trialled to overcome these tumour-evasion mechanisms. Next, we summarize recent advances in approaches to enhance CAR T cell activity and persistence over the past 10 years, including bispecific CAR T cell design and early evidence of efficacy. Lastly, we examine mechanisms of T cell infiltration and tumour regression, and discuss the strengths and weaknesses of different strategies to investigate T cell function in murine tumour models.

Keywords: CAR; CD8 T cells; cancer; checkpoint inhibitor; cytotoxic T lymphocytes; immunotherapy; tumour antigen.

Figure 1

MHC I aberrations in cancer. Tumours can be categorised into “Hard” or “Soft” lesions based on the nature of MHC I defects [19]. Mutations, deletions, or loss of heterozygosity result in irreversible structural defects in the MHC I pathway and can be categorised as “Hard” lesions. Downregulation or inhibition of gene expression result in reversible regulatory defects in the MHC I pathway and can be categorised as “Soft” lesions. Therapeutic approaches differ according to lesion type.

Figure 2

Murine models for evaluation of T cell-directed tumour immunotherapy. (A) Syngeneic models utilize murine-derived cancer cell lines grown and expanded in vitro and then injected into immunocompetent mice (commonly either subcutaneously or orthotopically); (B) Carcinogen-induced models utilize carcinogens such as ultraviolet light or chemicals to induce mutations resulting in the formation of de novo tumours; (C) Genetically engineered models involve transgenic technologies to induce depletion of tumour suppressor genes or expression of oncogenes, which drives autochthonous tumour growth; (D) Patient-derived xenograft (PDX) models involve collecting patient tumour material and injecting it into immunocompromised mice. Cancer cells obtained from tumour tissues can be injected alone or in concert with immune reconstitution by autologous immune cells or stem cells. Frequencies are implicated as: +++, frequently; ++, in some cases; +, rarely. Figure inspired by references [103,119].