CD8⁺ T effector targeted elimination of regulatory tumor stroma cells for improved immunotherapy

Mounting preclinical and clinical evidence over the past several decades implicated immune system in controlling malignancies. However, the translation of this knowledge into clinical benefit for cancer treatment has just recently been realized. A tumor-associated antigen (TAA) pulsed dendritic cell-based vaccine was the first immunotherapy product against cancer to be approved by FDA in the United States (1). This development not only overcame skepticisms about the potential of caner immunotherapy, but most importantly galvanized the field for the development of various forms of immunotherapies. A major setback for the cancer immunotherapy field has been the lack of comprehensive understanding of interactions between tumors and the immune system and how such interactions could be exploited for the development of effective immune therapies. The discovery that tumor uses a complex set of extrinsic and intrinsic mechanisms to evade the immune system paved the way for the design of effective immunotherapies with significant positive impact recently. For example, the discovery that tumors utilize the immune checkpoint receptors, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 (PD-1) pathway, to effectively evade T cell responses resulted in FDA-approved therapies against various cancer types using blocking antibodies to these molecules (2,3). The checkpoint blockers, however, are only effective for certain tumor types and the efficacy is limited to a fraction (~30%) of treated patient population with the responsive tumors. Combined therapy with both checkpoint blockers in advanced melanoma was recently reported to reach an objective response rate of 61% with drug-related adverse events of grade 3–4 in 54% of patients (4). The question is if complementary approaches, particularly TAA-based vaccine could further improve the efficacy of immune checkpoint blockers, reduce drug-related adverse effects, and broaden their application to unresponsive tumor types.