Radiotherapy Combined with Intralesional Immunostimulatory Agents for Soft Tissue Sarcomas

Abstract

Immunotherapy has shifted the treatment paradigm for many types of cancer. Unfortunately, the most commonly used immunotherapies, such as immune checkpoint inhibitors (ICI), have yielded limited benefit for most types of soft tissue sarcoma (STS). Radiotherapy (RT) is a mainstay of sarcoma therapy and can induce immune modulatory effects. Combining immunotherapy and RT in STS may be a promising strategy to improve sarcoma response to RT and increase the efficacy of immunotherapy. Most combination strategies have employed immunotherapies, such as ICI, that derepress immune suppressive networks. These have yielded only modest results, possibly due to the limited immune stimulatory effects of RT. Combining RT with immune stimulatory agents has yielded promising preclinical and clinical results but can be limited by the toxic nature of systemic administration of immune stimulants. Using intralesional immune stimulants may generate stronger RT immune modulation and less systemic toxicity, which may be a feasible strategy in accessible tumors such as STS. In this review, we summarize the immune modulatory effects of RT, the mechanism of action of various immune stimulants, including toll-like receptor agonists, and data for combinatorial strategies utilizing these agents.

Figure 1

Combined Effects of Radiotherapy and Intralesional Immunotherapy. (1) Radiotherapy can alter the TME by inducing vascular changes and increasing immune cell infiltration. (2) Radiotherapy increases immunogenic cell death (expression of calreticulin on cell surface and release of HMGB1) and the immunogenicity of surviving cancer cells through cell surface ligands (MHC1, FASL, stress ligands) which sensitize these tumor cells to immune mediated killing and secreted proinflammatory factors. (3) Immunogenic cell death and pro-inflammatory signals alter macrophage polarization and antigen presentation cell (APC) activation and antigen presenting function. (4) Activated APCs presenting neoantigens from dying irradiated cancer cells migrate to draining lymph nodes to activate T cells. (5) Activated T cells migrate to irradiated and non-irradiated tumors and enhance anti-tumor immunity. (6) Intratumoral injection of immune stimulants acts as an adjuvant and intensifies the radiotherapy in-situ vaccine effect by potentiating many of the mechanisms in 1-5. Created with BioRender.com.

Figure 2

Toll-like receptor (TLR) signaling. Cell surface and endosomal TLRs listed with their putative ligands. Downstream signaling pathways for the TLRs are outlined. Selected pharmaceutical agonists of TLRs are listed in cyan. Created with BioRender.com.