Overcoming barriers to effective immunotherapy: MDSCs, TAMs, and Tregs as mediators of the immunosuppressive microenvironment in head and neck cancer

Abstract

A significant subset of head and neck cancers display a T-cell inflamed phenotype, suggesting that patients with these tumors should respond to therapeutic approaches aimed at strengthening anti-tumor immune responses. A major barrier to the development of an effective anti-tumor immune response, at baseline or in response to immunotherapy, is the development of an immunosuppressive tumor microenvironment. Several well described mechanisms of effector immune cell suppression in the head and neck cancer microenvironment are discussed here, along with updates on current trials designed to translate what we have learned from pre-clinical and correlative clinical studies into improved responses in patients with head and neck cancer following immune activating therapies.

Keywords: Antigenicity; Immunity; Immunogenicity; Immunotherapy.

Figure 1. Myeloid Cell Differentiation and Recruitment

Myeloid-derived suppressor cells (MDSCs) accumulate under the influence of factors including GM-CSF, IL-6, IL-10, COX2, IL-1β, IDO, and VEGF, and are recruited to the tumor microenvironment by secreted CXCL1, IL-8, GM-CSF and CSF1. gMDSCs are terminally differentiated, while mMDSCs can further differentiate into macrophages and dendritic cells. Macrophages can also be recruited to the tumor microenvironment by CSF1.

Figure 2. Immunosuppressive Mechanisms of MDSCs

Under the influence of transcription factors STAT1, STAT3, STAT6 and HIF1α, MDSCs suppress TILs through a variety of mechanisms. Arg-1 inhibits TILs through depletion of arginine and activates Tregs. iNOS inhibits TILs through production of reactive oxygen and nitrogen species in addition to depletion of environmental arginine. MDSCs also secrete immunosuppressive cytokines IL-6 and IL-10, and express the immune checkpoint ligand PD-L1. Intracellular IDO expression has also been proposed as a mechanism of TIL inhibition through depletion of tryptophan and production of kynurenine metabolites.

Figure 3. Therapeutic Targeting of MDSCs

CXCR2 and CSFR1 antibodies inhibit chemotaxis of MDSCs to the tumor microenvironment. Vitamin D3 reduces MDSC numbers by promoting differentiation into macrophages and dendritic cells. PDE5 inhibitors increase intracellular cGMP, thereby inhibiting the immunosuppressive enzymes iNOS and Arg-1. Small molecule inhibitors of IDO, iNOS, Arg-1, and STAT3 have also been developed. Depleting antibodies targeted against Gr1 and Ly6G surface markers reduce MDSC numbers.

Figure 4. Tumor-Associated Macrophages

M2 macrophages inhibit T-cells through surface expression of HLA-G, CD80/86, and PDL1/PDL2. Like MDSCs macrophages secrete Arg1, which inhibits TILs through depletion of arginine. Macrophages also secrete immunosuppressive cytokines IL-1β, IL-6, IL-10 and TGFβ which inhibit TILs and activate Tregs. Surface expression of HLA-E also may inhibit NK cells in some cancer models. The central approach to targeting TAMs has been through the development of CSFR1 antagonists and antibodies.

Figure 5. Therapeutic Targeting of Regulatory T-Cells (Tregs)

In addition to secreting immunosuppressive cytokines IL-10 and TGFβ, Tregs inhibit TILs through surface expression of CTLA4 and CD39. Antibodies against surface molecules CTLA4, CCR4, and CD25 have all been shown to deplete Tregs in various cancer models. Agonist antibodies against GITR and OX40 stimulate effector T-cells in addition to inhibiting Treg function.