Adoptive immunotherapy of cancer using CD4(+) T cells

Abstract

CD4(+) T cells are central to the function of the immune system but their role in tumor immunity remains underappreciated. It is becoming clear that there is an enormous diversity of CD4(+) T cell polarization patterns including Th1, Th2, Th17, and regulatory T cells (Tregs). These functionally divergent T cell subsets can have opposing effects -- they can trigger tumor rejection or inhibit treatment after adoptive cell transfer. Some polarized CD4(+) cells have plasticity, and their phenotypes and functions can evolve in vivo. Recent advances in understanding of polarization and differentiation of lymphocytes, as well as some intriguing developments in the clinic, indicate that the use of CD4(+) T cell subsets in the immunotherapy of cancer has unrealized potential.

Figure 1

Recognition of poorly immunogenic tumor via endogenous and exogenous pathways. Relying on presentation of antigens by a genetically unstable tumor can result in unreliable and suboptimal responses. Defects in the antigen processing via the endogenous pathway, including β₂-microglobulin, TAP1, and TAP2 deficiencies and loss of MHC chains can affect a tumor cell’s ability to process and present MHC class I-restricted antigens. These defects can render CD8⁺ cytotoxic cells unable to eliminate tumors cells, leading to preferential survival of escape variants. Direct recognition of tumors via MHC class II is equally dependant on the unstable autophagy and antigen processing by cancer cells. Normal professional antigen presenting cells (APCs) infiltrating the tumor or present in the draining lymph nodes are less subject to derangements of their antigen processing and presenting machinery. APC continually monitor the environment, take up tumor-derived material and efficiently present it to CD4⁺ T cells even if the tumor cells lost the endogenous ability to process antigens.

Figure 2

A proposed model for Th cell subset evolution in antitumor immunity. Th cells can play a central role in tumor rejection by recognizing and killing malignant cells directly. Indirect recognition of tumor-associated antigens can result in the activation of antigen presenting cells (APCs), which in turn are capable of activating cytotoxic CD8⁺ T cells and natural killer (NK) cells. In vitro polarized tumor-specific Th17 T cells express the transcription factor ROR-γt and secrete an array of cytokines, including proinflammatory IL-17A and IL17F. Th17-polarized cells are plastic and can evolve into t-bet-expressing Th1-like population secreting IFN-γ that can eliminate tumor after adoptive transfer. Acquisition of t-bet might represent the maturation into a more terminally differentiated phenotype that is closer to senescence and/or apoptosis. Thus, early (in vitro) expression of t-bet during Th1 polarization might be less desirable as it generates cells less likely to survive upon adoptive transfer. Th17-polarized cells are closely related to induced-FOXP3⁺ regulatory cells (iTreg), which might negatively influence antitumor immunity. There is a considerable plasticity between iTreg and Th17 cells.