Immune recognition of irradiated cancer cells

Abstract

Summary Ionizing irradiation has been extensively employed for the clinical management of solid tumors, with therapeutic or palliative intents, for decades. Until recently, radiation therapy (RT) was believed to mediate antineoplastic activity mostly (if not only) as a consequence of cancer cell-intrinsic effects. Indeed, the macromolecular damage imposed to malignant cells by RT initiates one or multiple signal transduction cascades that drive a permanent proliferative arrest (cellular senescence) or regulated cell death. Both these phenomena show a rather linear dose-response correlation. However, RT also mediates consistent immunological activity, not only as an “on-target effect” originating within irradiated cancer cells, but also as an “off-target effect” depending on the interaction between RT and stromal, endothelial and immune components of the tumor microenvironment. Interestingly, the immunological activity of RT does not exhibit linear dose-response correlation. Here, we discuss the mechanisms whereby RT alters the capacity of the immune system to recognize and eliminate irradiated cancer cells, either as an “on-target” or as on “off-target” effect. In particular, we discuss the antagonism between the immunostimulatory and immunosuppressive effects of RT as we delineate combinatorial strategies to boost the former at the expenses of the latter.

Linking cellular stress responses to systemic homeostasis

“…This increased recognition is particularly important for the elimination of malignant cells that express antigens potentially detectable by the immune system 17 . Moreover, DNA damage generally favours the upregulation of multiple ligands for NK cell activatory receptors, such as NKG2D type II integral membrane protein also known as KLRK1) and DNAX accessory molecule 1 (DNAM1; also known as CD226 (REFs 18,19 )). The increased expression of these molecules is particularly relevant when genetic integrity cannot be restored, resulting in cell senescence 20 .…”

Sublethal Radiation Affects Antigen Processing and Presentation Genes to Enhance Immunogenicity of Cancer Cells

“…In 1971, Natale et al were among the first to show that sublethal radiation renders cancer cells more immunogenic [12]. The recent enthusiasm on the synergy of radiotherapy and immunotherapy has renewed interest in the mechanisms by which sublethal radiation enhances cancer immunogenicity [13]. We sought to investigate the universality of such mechanisms using a panel of human cancer cell lines.…”

Corrigendum

“…In this article, the authors recognized some inaccurate and/or potentially misleading sentences that they would like to amend, for the sake of factual precision. In particular: in page 220: left column, the sentence “…as a purely cancer cell‐intrinsic…” should read “…mainly as a cancer cell‐intrinsic…”; right column, the sentence “…is generally incapable…” should read “…is sometimes incapable…”. in page 221: left column, the sentence “…two fractions of 2 Gy each…” should read “…two fractions of 4 Gy each…”; right column: the word “non‐lytic” should read “non‐cytotoxic” in both paragraphs; the word “sublethal” should read “sub‐cytotoxic”; the sentence “…mediator (most likely IFNB1) released by irradiated cells” should read “…mediator released by irradiated cells, although these radiation doses are not clinically relevant”; the sentence “…which fails to promote RCD…” should read “…which did not promote RCD…”. in page 222 right column, the sentence “Lethal RT doses (in particular when delivered according to a fractionated schedule) promote…” should read “Cytotoxic RT can promote…”. in page 223 left column, the words “lethal doses” should read “cytotoxic doses”; right column, the sentence “Mouse pancreatic carcinoma Myc‐CaP cells…” should read “Mouse prostate carcinoma Myc‐CaP cells…”. in page 225: left column, the sentence “…sensitivity of T REG cells…” should read “…sensitivity of mouse (but not rat and human) 83,84 T REG cells…”; right column, the sentence “Thus, some DCs subsets (including Langerhans cells) may…” should read “Thus, although the clinical relevance of the latter experimental scenario is limited, some DCs subsets (perhaps including Langerhans cells) may…”. in page 226 left column, the sentence “Combining the TGFB1‐neutralizing antibody fresolimumab…” should read “Combining the pan‐TGFB‐neutralizing antibody 1D11…”. …”