Stimulating Innate Immunity to Enhance Radiation Therapy-Induced Tumor Control

Abstract

Novel ligands that target Toll-like receptors and other innate recognition pathways represent a potent strategy for modulating innate immunity to generate antitumor immunity. Although many of the current clinically successful immunotherapies target adaptive T-cell responses, both preclinical and clinical studies suggest that adjuvants have the potential to enhance the scope and efficacy of cancer immunotherapy. Radiation may be a particularly good partner to combine with innate immune therapies, because it is a highly efficient means to kill cancer cells but may fail to send the appropriate inflammatory signals needed to act as an efficient endogenous vaccine. This may explain why although radiation therapy is a highly used cancer treatment, true abscopal effects-regression of disease outside the field without additional systemic therapy-are extremely rare. This review focuses on efforts to combine innate immune stimuli as adjuvants with radiation, creating a distinct and complementary approach from T cell-targeted therapies to enhance antitumor immunity.

Figure 1. Distribution of innate receptors across cell types in the ImmGen dataset

The graph shows gene expression of innate receptors in sorted cell types clustered into broad immune populations. Expression of each gene is normalized across cell populations and color-coded according to the key. There is significant variation in expression of innate sensors across immune cells. While receptors such as TLR4 are most highly expressed by macrophages and neutrophils, TLR9 shows extended expression into dendritic cells and B cells. Broadly, T cells exhibit low expression of TLR. By contrast, the innate sensor STING and the type I IFN receptor are very evenly expressed across many cell populations. This analysis is a result of data assembled by the ImmGen Consortium. Full analysis of gene expression patterns can be visualized at www.immgen.org.

Figure 2. Effect of adjuvant on immune cell relationships in the tumor and draining lymph nodes

In the absence of adjuvant, cell death mediated by radiation therapy drives M2 responses that suppress DC maturation and effector T cell function. Innate immune adjuvants can drive proinflammatory M1 responses, enhance DC cross presentation of tumor antigens to T cells in the lymph node in a supportive cytokine environment, and support effector T cell control of residual disease.