Radio-Immunotherapy-Induced Immunogenic Cancer Cells as Basis for Induction of Systemic Anti-Tumor Immune Responses – Pre-Clinical Evidence and Ongoing Clinical Applications

Abstract

Radiotherapy (RT) primarily aims to locally destroy the tumor via the induction of DNA damage in the tumor cells. However, the so-called abscopal, namely systemic and immune–mediated, effects of RT move over more and more in the focus of scientists and clinicians since combinations of local irradiation with immune therapy have been demonstrated to induce anti-tumor immunity. We here summarize changes of the phenotype and microenvironment of tumor cells after exposure to irradiation, chemotherapeutic agents, and immune modulating agents rendering the tumor more immunogenic. The impact of therapy-modified tumor cells and damage-associated molecular patterns on local and systemic control of the primary tumor, recurrent tumors, and metastases will be outlined. Finally, clinical studies affirming the bench-side findings of interactions and synergies of radiation therapy and immunotherapy will be discussed. Focus is set on combination of radio(chemo)therapy (RCT) with immune checkpoint inhibitors, growth factor inhibitors, and chimeric antigen receptor T-cell therapy. Well-deliberated combination of RCT with selected immune therapies and growth factor inhibitors bear the great potential to further improve anti-cancer therapies.

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

“…The biological or therapeutic contexts where apoptosis or necrosis can evoke tolerogenicity or immunogenicity have been described. 30 However, similar knowledge is seldom available for other cell death pathways 2 such as necroptosis, autophagic cell death, mitotic catastrophe, parthanatos and ferroptosis (Box 1) -a gap in knowledge that requires urgent attention. For instance, necroptosis 31 and autophagic cell death 32 offer a therapeutic alternative to kill apoptosis-resistant cancer cells, 33 but recognition and clearance of necroptotic/autophagic cells by phagocytes is not completely understood.…”

“…[97][98][99] In the future, it would be crucial to find new targets for ICTs that are exploited by tolerogenic phagocytosis. 98,99 Moreover, considering that currently many clinically applied anticancer therapies tend to induce TCD, and thereby facilitate tolerogenic phagocytosis (Table 1), 30 it would be crucial to combine these with ICTs ( Figure 2). 100 Clinical applications of pro-phagocytic and antiphagocytic determinants.…”

Mathematical Modeling of Cancer Immunotherapy and Its Synergy with Radiotherapy

“…Despite outstanding progress in melanoma and lung cancers, a majority of patients will nevertheless fail in achieving long-lasting responses. Associating radiotherapy with immunotherapy has shown synergistic effect and is now considered as a promising strategy to stretch both response and survival at bedside (2). However, combining radiotherapy and immunotherapy can be done following a variety of different modalities.…”

Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy

“…Following double-stranded breaks in DNA, the RAD50/NBS/MRE11 complex rapidly translocates to the sites of the breakage, forming aggregated nuclear foci until the break is repaired, for example, IRIF (18,20,23,25). Thus, RAD50 can be used as a specific identifier of cells that have been exposed to high levels of radiation, acting as a biological tag of cells from patients that have been directly exposed to radiation targeted to a tumor mass (18)(19)(20)(21)(22)(23)(24)(26)(27)(28).…”