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. 2015 Sep 1;1(1):66-75.
doi: 10.1016/j.trecan.2015.07.008.

Immune response to cancer therapy: mounting an effective antitumor response and mechanisms of resistance

Terry R Medler  1 , Tiziana Cotechini  1 , Lisa M Coussens  2
Affiliations

Immune response to cancer therapy: mounting an effective antitumor response and mechanisms of resistance

Terry R Medler et al. Trends Cancer. .

Abstract

Chemotherapy and radiotherapy have been extensively used to eradicate cancer based on their direct cytocidal effects on rapidly proliferating tumor cells. Accumulating evidence indicates that these therapies also dramatically affect resident and recruited immune cells that actively support tumor growth. We now appreciate that mobilization of effector CD8+ T cells enhances efficacy of chemotherapy and radiotherapy; remarkable clinical advances have been achieved by blocking regulatory programs limiting cytotoxic CD8+ T cell activity . This review discusses immune-mediated mechanisms underlying efficacy of chemotherapy and radiotherapy, and provides a perspective on how understanding tissue-based immune mechanisms can be used to guide therapeutic approaches combining immune and cytotoxic therapies to improve outcomes for a larger subset of patients than currently achievable.

Keywords: Checkpoints; Chemotherapy; Immunosuppression; Macrophage; Radiotherapy.

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Figures

Key Figure, Figure 1
Key Figure, Figure 1
Strategies to bolster antitumor immunity. (A) Apoptotic tumor cells release high-mobility group box 1 (HMGB1), ATP, heat shock proteins (HSPs), and other danger-associated molecular patterns (DAMPs) into the stroma following chemotherapy and/or radiation therapy. DAMPs signal through TLRs on DCs and lead to maturation, trafficking to lymph nodes, and cross-presentation of tumor antigens to cytotoxic T cells. (B) CD8+ T cells present within the TME are often rendered tolerant via immunosuppressive factors released by M2 macrophages or a TH2 microenvironment, as well as expression of immune checkpoint inhibitors by various cells within the microenvironment. By utilizing cancer-type specific immunotherapy, macrophages can be repolarized such that CD8+ T cells can be recruited and activated within the TME. (C) Expression of checkpoint inhibitors, such as PD-1, PD-L1, and CTLA-4, limits activity of CD8+ T cells. By blocking checkpoint molecules, CD8+ T cells are able to mount a cytoloytic attack against tumor antigens. By targeting several or all of the pathways outlined above, the immunosuppressive TME can become immune stimulatory and likely offer potent and durable anti-tumor immune responses in the clinic.
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