Vaccines targeting helper T cells for cancer immunotherapy

Abstract

There are compelling arguments for designing cancer vaccines specifically to induce CD4⁺ helper T cell responses. Recent studies highlight the crucial role of proliferating, activated effector memory Th1 CD4⁺ T cells in effective antitumor immunity and reveal that CD4⁺ T cells induce more durable immune-mediated tumor control than CD8⁺ T cells. CD4⁺ T cells promote antitumor immunity by numerous mechanisms including enhancing antigen presentation, co-stimulation, T cell homing, T cell activation, and effector function. These effects are mediated at sites of T cell priming and at the tumor microenvironment. Several cancer vaccine approaches induce durable CD4⁺ T cell responses and have promising clinical activity. Future work should further optimize vaccine adjuvants and combination therapies incorporating helper peptide vaccines.

Figure 1. Role of helper T cells in priming of tumor specific effector T cells

Step 1. Vaccination with helper peptides allows antigen presenting cells (APCs) to take up tumor specific helper peptides in addition to tumor antigen directly from dying tumor cells. Step 2). APCs migrate to the lymph node where they interact with CD4 T cells through MHC class II molecules. Step 3). CD40 on the CD4 T cells ligates CD40L to mature the APC, which leads to enhanced MHC class I expression as well as costimulatory molecules CD70 and CCL3 and CCL4. Step 4) The chemokines recruit CD8 T cells to the complex, and binding the MHC molecules with costimulation induces optimal effector priming. The primed effectors proliferate and are capable of trafficking to the tumor site.

Figure 2. Role of CD4 T cells in the tumor microenvironment

Step 1). CD4 T cells can home to the tumor where they can interact with tumor cells when they express MHC class II. When activated Th1 CD4+ cells produce IFNγ. Step 2). IFNγ enhances MHC expression by tumor cells. Additionally, it induces CXCL9 and CXCL10 expression by the vasculature, to optimally recruit CD8 effector T cells to the tumor site. Step 3). Some CD4 T cells also are capable of direct tumor cell killing through FasL and TRAIL interactions as well as T cell receptor mediated cytotoxicity. Additionally, the T cells produce IL-2 which supports CD8 effector T cells in survival, proliferation and cytotoxic activity.

Figure 3. Association of IFNγ expression with survival in melanoma

Data from the Cancer Genome Atlas (TCGA) were interrogated through cbioportal.org for 459 patients. Overexpression of IFNγ in the tumor microenvironment (z > 0.5, 11% of patients), was associated with enhanced overall survival (148 vs 69 months median survival, p = 0.011). Similar significant differences were evident with z scores of 0.8, 1, 1.2, 1.5 (p < 0.006 to p = 0.02, data not shown).