Harnessing Antitumor CD4+ T Cells for Cancer Immunotherapy

Abstract

Over the past decades, CD4⁺ T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4⁺ T cells during antitumor immunity. CD4⁺ T cells can either suppress or promote the antitumor cytotoxic CD8⁺ T cell responses, either in secondary lymphoid organs or in the tumor. In this review, we provide an overview of the multifaceted role of different CD4⁺ T cell subsets in cancer immune response and their contribution during cancer therapies. Specifically, we focus on the latest progress regarding the impact of CD4⁺ T cell modulation on immunotherapies and other cancer therapies and discuss the prospect for harnessing CD4⁺ T cells to control tumor progression and prevent recurrence in patients.

Keywords: CD4+ T cells; adoptive cell transfer; cancer immunotherapy; cancer vaccine; immune checkpoint inhibitors.

Figure 1

CD4⁺ T cell subsets in the tumor microenvironment (TME). Th1 cells (in red) exert a prominent antitumor activity. These cells produce various cytokines (IFN-γ, TNF-α, IL-2 and IL-21) to induce CTL help, CAF and TAM activation promoting immune cell recruitment such as CD8⁺ cytotoxic T lymphocytes (CTL) and Natural Killer (NK) cells that mediate tumor-killing activity. CD4⁺ T cells with cytotoxic activity (in orange) secrete GZMB and PFN and directly kill target cells. Th17 cells (in green) by producing IL-17 cytokine induce the polarization of M1 macrophage and the recruitment of antitumor immune cells (NK and CD8⁺ T cells) and Myeloid-derived suppressor cells (MDSC). Th2 cells (in yellow) present an ambivalent role in cancer. These cells contribute to antitumor responses by inducing NK cell activation (IL-4 production) and protumor responses by promoting M2 macrophage polarization (IL-4 production) and suppressive IL-10 producing-B cell activation (IL-13 production). Treg cell (in pink) presence within the tumor impedes antitumor responses by suppressing effector T cell activity through immunosuppressive cytokine production (TGFβ, IL-10 and IL-35), IL-2 consumption, antigen-presenting cell (APC) suppression and ATP- adenosine conversion. Tumor progression or regression depends on the overall effect of the complex cellular network within TME. DC, dendritic cell; CAF, cancer-associated fibroblasts; TAM, tumor-associated macrophage; GZM, granzyme; PFN, perforin; TNF-α, tumor necrosis factor-α.

Figure 2

Harnessing CD4⁺ T cells to improve cancer therapy. While CD4⁺ T cell subsets function during antitumor response has become more appreciated, cancer therapy strategies might benefit from including approaches to modulate CD4⁺ T cell subset. Conventional therapies, chemotherapy (CT) and radiotherapy (RT) have an impact on CD4⁺ T cell response modulation. Cyclophosphamide (CTX) results in the development of robust Th1 antitumor immunity and immunosuppressive Treg cell depletion. Tumor-specific Th1 subset increases after DCF (Docetaxel, Cisplatin and 5-fluorouracil) regimen. Neoadjuvant CT promotes antitumor CD8⁺ and CD4⁺ T Resident Memory (TRM) cells. The combination of CT and RT induces Th1 polarized immune signature while RT and anti-PD1 immunotherapies result in Th1 cell activation. Immune checkpoint blockade (ICB) relies on blocking antibodies able to inhibit immune checkpoint receptors axis such as PD-1/PD-L1 ((Nivolumab/Atezolizumab) and/or CTLA-4 (Ipilimumab), which provide effector CD4⁺ T cell expansion resulting in efficacious CD8⁺ T cell response. Adoptive cell transfer of T cells includes tumor-infiltrating lymphocytes (TILs) transfer and genetically engineered T cells transfer. Both strategies should include CD4⁺ T cells to provide help at the tumor site. Thus, transferred ex vivo expanded TILs (CD4⁺ and CD8⁺ T cells) or Chimeric Antigen Receptor (CAR) T cells enhance antitumor responses. Peptides used in therapeutic cancer vaccines including MHC-II epitopes (Her2-neu, UCP2 and UCP4 hTERT, NEO-PV01) are able to activate CD4⁺ T cells and rely on help signals to CD8⁺ T cells. Targeting epigenetics regulators such as EZH2 and DNMT markers could alter Treg functionality and induce antitumor Th1 responses. Otherwise, targeting metabolism programming (glucose, glutamine, Indoleamine 2,3-dioxygenase IDO…) could boost effector T cell response and inhibit Treg polarization. EZH2, enhancer of zeste homolog 2; DNMT, DNA methyltransferase 1.