Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy

Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications – such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer – clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of anti-tumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of “precision” cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted – and personalized – approach combining DC-based vaccination with adjunctive strategies.


Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA , USA ; Rena Rowen Breast Center, Hospital of the University of Pennsylvania , Philadelphia, PA , USA.

Vaccination Strategies

Vaccination strategies incorporating the immunodominant HLA-A2-restricted HER2/neu-derived peptide 369-377 (HER2369-377) are increasingly utilized in HER2/neu-expressing cancer patients. The failure of postvaccination HER2369-377-specific CD8(+) T cells to recognize HLA-A2(pos)HER2/neu-expressing cells in vitro, however, has been attributed to impaired MHC class I/HLA-A2 presentation observed in HER2/neu-overexpressing tumors. We reconcile this controversy by demonstrating that HER2369-377 is directly recognized by high functional-avidity HER2369-377-specific CD8(+) T cells-either genetically modified to express a novel HER2369-377 TCR or sensitized using HER2369-377-pulsed type 1-polarized dendritic cells (DC1)-on class I-abundant HER2(low), but not class I-deficient HER2(high), cancer cells. Importantly, a critical cooperation between CD4(+) T-helper type-1 (Th1) cytokines IFNγ/TNFα and HER2/neu-targeted antibody trastuzumab is necessary to restore class I expression in HER2(high) cancers, thereby facilitating recognition and lysis of these cells by HER2369-377-specific CD8(+) T cells. Concomitant induction of PD-L1 on HER2/neu-expressing cells by IFNγ/TNF and trastuzumab, however, has minimal impact on DC1-sensitized HER2369-377-CD8(+) T-cell-mediated cytotoxicity. Although activation of EGFR and HER3 signaling significantly abrogates IFNγ/TNFα and trastuzumab-induced class I restoration, EGFR/HER3 receptor blockade rescues class I expression and ensuing HER2369-377-CD8(+) cytotoxicity of HER2/neu-expressing cells. Thus, combinations of CD4(+) Th1 immune interventions and multivalent targeting of HER family members may be required for optimal anti-HER2/neu CD8(+) T-cell-directed immunotherapy.


Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Rena Rowen Breast Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.