Immune Effects of Chemotherapy, Radiation, and Targeted Therapy and Opportunities for Combination With Immunotherapy

Abstract

There have been significant advances in cancer treatment over the past several years through the use of chemotherapy, radiation therapy, molecularly targeted therapy, and immunotherapy. Despite these advances, treatments such as monotherapy or monomodality have significant limitations. There is increasing interest in using these strategies in combination; however, it is not completely clear how best to incorporate molecularly targeted and immune-targeted therapies into combination regimens. This is particularly pertinent when considering combinations with immunotherapy, as other types of therapy may have significant impact on host immunity, the tumor microenvironment, or both. Thus, the influence of chemotherapy, radiation therapy, and molecularly targeted therapy on the host anti-tumor immune response and the host anti-host response (ie, autoimmune toxicity) must be taken into consideration when designing immunotherapy-based combination regimens. We present data related to many of these combination approaches in the context of investigations in patients with melanoma and discuss their potential relationship to management of patients with other tumor types. Importantly, we also highlight challenges of these approaches and emphasize the need for continued translational research.

Figure 1

T-cell activation is regulated by antigen presentation, as well as stimulatory and inhibitory co-receptors. (A) Overview of the MHC I and II antigen presentation and processing pathways. Canonical pathways of MHC I antigen presentation allow display of intracellular proteins following processing and transport to circulating CD8⁺ T lymphocytes. Canonical MHC II antigen presentation allows display of antigens derived from the extracellular environment to circulating CD4⁺ T lymphocytes. (B) Signals required for proper T-cell activation. Both CD4⁺ and CD8⁺ T cells are activated following interaction with signal 1 provided through presentation of MHC I or II/peptide complexes at the cell surface with the T-cell receptor (TCR), as well as signal 2 supplied by interaction of CD80/CD86 costimulation molecules expressed on antigen-presenting cells (APCs) with CD28 expressed on T cells. Only in presence of both signals will naive T cells be activated. Following activation, T cells may recognize and kill cells presenting only signal 1 (MHC/peptide). (C) Signaling pathways engaged following interaction of T cells with signals 1 and 2. T cells stimulated through the TCR engage MAPK pathway signaling, which results in production of cytokines such as IL-2. Signal 2 targets PI3K/AKT signaling, through which T-cell survival and proliferation result. Both signals are crucial for initial T-cell activation. (D) Overview of the receptors and ligands expressed on T cells and APCs, which may influence T-cell activation upon interaction. Several of these receptors may be expressed on T cells following T-cell activation as a mechanism to inhibit T-cell activation and prevent autoimmune disease.

Figure 2

Impact of immunotherapy, targeted chemotherapy, and radiation therapy on tumors and the immune system as monotherapy and in combination. The top row depicts known impacts of immunotherapies through targeting checkpoint inhibitors, cytokine treatment, or adoptive cell therapy on tumor mass, and immune cell function in comparison to without treatment (top left). The left column depicts the known effects of other forms of therapy, such as targeted therapy, chemotherapy, and radiation therapy, on tumor mass and immune cell function in comparison to without treatment (top left). Intersections between forms of treatment represent the extrapolated effect on combining immunotherapies with other forms of therapy, based on known effects of regimens individually.