The anticancer immune response: indispensable for therapeutic success?

Abstract

Although the impact of tumor immunology on the clinical management of most cancers is still negligible, there is increasing evidence that anticancer immune responses may contribute to the control of cancer after conventional chemotherapy. Thus, radiotherapy and some chemotherapeutic agents, in particular anthracyclines, can induce specific immune responses that result either in immunogenic cancer cell death or in immunostimulatory side effects. This anticancer immune response then helps to eliminate residual cancer cells (those that fail to be killed by chemotherapy) or maintains micrometastases in a stage of dormancy. Based on these premises, in this Review we address the question, How may it be possible to ameliorate conventional therapies by stimulating the anticancer immune response? Moreover, we discuss the rationale of clinical trials to evaluate and eventually increase the contribution of antitumor immune responses to the therapeutic management of neoplasia.

Figure 1. Mechanisms of the impact of conventional anticancer therapies on immune responses.

Anticancer therapeutics can inhibit suppressive mechanisms of tumor-induced immune tolerance (blue circle), boost T and/or B cell responses (pink circle), or stress tumor cells in such a way that tumor cells become immunogenic and sensitive to lysis (yellow circle). The main drugs driving these effects are also shown. Cyclophosphamide at low doses, gemcitabine, and all-trans-retinoic acid (ATRA) act on immunosuppressive cells such as Tregs or myeloid suppressor cells (MdSC) to facilitate tumor attack by conventional effectors (Tconv). Pharmacological inhibition of MdSCs can also be achieved by nitroaspirin (96), sildenafil (97), and biphosphonate (98). Androgen deprivation boosts T and B cell responses. Strategies leading to lymphodepletion allow the establishment of memory effector T cells efficient in long-term protection against tumor cells. Tyrosine kinase inhibitors boost DC/NK cell crosstalk. The proteasome inhibitor bortezomib induces myeloma cell–surface expression of the molecular chaperone protein HSP90, which leads to DC uptake, antigen processing, and DC maturation. Anthracyclines, oxaliplatin, and irradiation promote tumor membrane expression of CRT and release of HMGB1 by tumor cells, which are required events for DC-mediated phagocytosis of dying tumors and cross-presentation of tumor antigens to T cells, respectively. Inhibitors of histone deacetylases (HDACs) promote the expression of NKG2D ligands (NKG2DL), sensitizing the tumor cell to NK cell–mediated lysis. Tumor cells exposed to x-rays express increased numbers of MHC class I molecules, tumor antigens, and Fas, favoring CTL attack. Flavanoid-mediated production of chemokines favors attraction of immune effectors into tumor beds. Ideally, an appropriate combination of chemotherapeutic agents could achieve all of these three types of beneficial effects.

Figure 2. Steps required for successful cancer immunotherapy.

The immune system of cancer-bearing individuals suffers from tumor-induced tolerance, which should be alleviated (Step 1) before induction of an active immune response with tumor vaccines (Step 2). Some evidence suggests that prior vaccination (Step 2) favors the antitumor effects of chemotherapeutic agents (Step 3). Cell death triggered by chemotherapy or radiotherapy (Step 3) should then be rendered immunogenic via addition of compounds that enhance calreticulin expression at the tumor cell membrane (Step 4). To overcome putative TLR4 host defects, which can compromise the developing immune response, administration of chloroquine is indicated (Step 5). Finally, immune adjuvants should be given to sustain and enhance the ensuing antitumor immune response (Step 6). Potential mediators at each step are listed. GMTV, genetically modified tumor vaccines; PP1-GADD34, protein phosphatase 1 complexed to GADD34; IL-15 sushi, sushi domain of soluble IL-15 receptor α (99).