The Multifaceted Role of Th1, Th9, and Th17 Cells in Immune Checkpoint Inhibition Therapy

Abstract

During the last decade, immune checkpoint inhibition (ICI) has become a pillar of cancer therapy. Antibodies targeting CTLA-4 or PD-1/PD-L1 have been approved in several malignancies, with thousands of clinical trials currently underway. While the majority of cancer immunotherapies have traditionally focused on enhancing cytotoxic responses by CD8⁺ or NK cells, there are clear evidences that CD4⁺ T cell responses can modulate the immune response against tumors and influence the efficacy of ICI therapy. CD4⁺ T cells can differentiate into several subsets of helper T cells (Th) or regulatory T cells (Treg), with a wide range of effector and/or regulatory functions. Importantly, different Th subsets may have different and sometimes contrasting roles in the clinical response to ICI therapy, which in addition may vary depending on the organ and tumor niche. In this review, we discuss recent evidence that highlights how ICI therapy impacts Th1, Th9, and Th17 cells and vice versa. These data might be important designing better interventions that unleash the full potential of immune response against cancer.

Keywords: CTLA-4; PD-1; T helper (Th) cell; Th1; Th17; Th9; cancer therapy; immune checkpoint inhibition.

Figure 1

CD4⁺ T cell differentiation in different helper subsets. Naïve CD4⁺ T cells (Th0) can differentiate into different subsets of T helper (Th) cells. This differentiation depends on the cytokine milieu that is present during antigen recognition and TCR stimulation. In response to these signals, naïve CD4⁺ T cells upregulate key transcription factors that control subset differentiation, which in turn determines the production of signature cytokines that mediate the effector function of each Th subset.

Figure 2

The importance of ICOS⁺ Th1 cells in ICI therapy. Genetic absence of CTLA-4 or blocking with anti–CTLA-4 antibody induces the differentiation of ICOS⁺ Th1-like cells. Additionally, concomitant PD-1 blockade may promote the proliferation of these ICOS⁺ T cells, which have the ability to migrate to tumors. In the tumor microenvironment, ICOS pathway activation by APCs or tumor cells induces positive co-stimulation, while CTLA-4 and/or PD-1 blockade prevents negative co-stimulatory signals. The result is a population of tumor-infiltrating CD4⁺ T cells with high expression of IFN-γ and TNF-α, which can recognize tumor antigens and boost the antitumor immune response. APC, Antigen presenting cell; CTLA-4, Cytotoxic T cell antigen 4; ICOS, Inducible co-stimulator; IFN, Interferon; PD-1, Programmed death 1; TNF, Tumor necrosis factor.