The interplay of immunotherapy and chemotherapy: harnessing potential synergies

Abstract

Although cancer chemotherapy has historically been considered immune suppressive, it is now accepted that certain chemotherapies can augment tumor immunity. The recent success of immune checkpoint inhibitors has renewed interest in immunotherapies, and in combining them with chemotherapy to achieve additive or synergistic clinical activity. Two major ways that chemotherapy promotes tumor immunity are by inducing immunogenic cell death as part of its intended therapeutic effect and by disrupting strategies that tumors use to evade immune recognition. This second strategy, in particular, is dependent on the drug, its dose, and the schedule of chemotherapy administration in relation to antigen exposure or release. In this Cancer Immunology at the Crossroads article, we focus on cancer vaccines and immune checkpoint blockade as a forum for reviewing preclinical and clinical data demonstrating the interplay between immunotherapy and chemotherapy.

Figure 1. Mechanisms of immunogenic tumor cell death induced by chemotherapy

Certain chemotherapy agents can cause immunogenic cell death through diverse pathways. (A) Anthracyclines, cyclophosphamide, and oxaliplatin induce immunogenic cell death through the release of tumor antigens, the translocation of CRT (an eat me signal for phagocytosis by DCs) to the cell surface, and the secretion of the danger-associated molecules HMGB1 and ATP (a find me signal for phagocytosis by DCs). These cell death-associated molecules bind their respective receptors, the calreticulin receptor (CRTR), the TLR4 receptor (TLR4R), and the P2RX7 receptor. This results in activation of the NRLP3 inflammasome, the production of pro-IL1β, DC maturation, and the secretion of IL1β to support the evolution of tumor-specific CD8⁺ T cells. (B) Tumor cell death induced by anthracylines results in the release of dsRNA, which binds to TLR3 and results in the tumor cell autonomous secretion of type I IFNs. This pathway is analogous to the response to viral infection, and supports the evolution of tumor immunity. Abbreviations: CRT=calreticulin; DC=dendritic cell; HMGB1=high mobility binding box 1; ATP=adenosine triphosphate; TLR=toll-like receptor; IFN=interferon; IL=interleukin; NRLP3=inflammasome.

Figure 2. Chemotherapy modulates tumor immunity by mechanisms distinct from immunogenic cell death

Various chemotherapy drugs can modulate the activity of distinct immune cell subsets, or the immune phenotype of tumor cells through enhancing antigen presentation, enhancing expression of co-stimulatory molecules including B7.1 (CD80) and B7.2 (CD86), downregulating checkpoint molecules such as programmed death-ligand 1 (PD-L1,) or promoting tumor cell death through the fas, perforin, or granzyme B pathways. Abbreviations; DC=dendritic cell; MDSC=myeloid-derived suppressor cell; Treg=regulatory T cell; T_H=T helper cell. Reviewed in greater detail in (2).