T Cell Immunity Induced by Live, Necrotic, and Apoptotic Tumor Cells

Abstract

The rules that govern the engagement of antitumor immunity are not yet fully understood. Ags expressed by tumor cells are prone to induce T cell tolerance unless the innate immune system is activated. It is unclear to what extent tumors engage this second signal link by the innate immune system. Apoptotic and necrotic (tumor) cells are readily recognized and phagocytosed by the cells of the innate immune system. It is unknown how this affects the tumor’s immunogenicity. Using a murine melanoma (B16m) and lymphoma (L5178Y-R) model, we studied the clonal sizes and cytokine signatures of the T cells induced by these tumors in syngeneic mice when injected as live, apoptotic, and necrotic cells. Both live tumors induced a type 2 CD4 cell response characterized by the prevalent production of IL-2, IL-4, and IL-5 over IFN-γ. Live, apoptotic, and necrotic cells induced CD4 (but no CD8) T cells of comparable frequencies and cytokine profiles. Therefore, live tumors engaged the second signal link, and apoptotic or necrotic tumor cell death did not change the magnitude or quality of the antitumor response. A subclone of L5178Y-R, L5178Y-S cells, were found to induce a high-frequency type 1 response by CD4 and CD8 cells that conveyed immune protection. The data suggest that the immunogenicity of tumors, and their characteristics to induce type 1 or type 2, CD4 or CD8 cell immunity is not primarily governed by signals associated with apoptotic or necrotic cell death, but is an intrinsic feature of the tumor itself.

Virus-mediated oncolysis induces danger signal and stimulates cytotoxic T-lymphocyte activity via proteasome activator upregulation

“…Several groups have debated whether necrotic or apoptotic cells can stimulate DCs to cross-present cellderived peptides, with subsequent enhancement of tumor immunogenicity. Furthermore, it has been reported recently that the immunogenicity of tumors is not regulated by signals associated with apoptotic or necrotic cell death, but is an intrinsic feature of the tumor itself (Bartholomae et al, 2004). Our data indicate that viral oncolysis could efficiently load tumor antigen on DCs, and then generate CTL response as judged from the production of cytokines.…”

Photodynamic therapy and anti-tumour immunity

“…Many studies have examined the relationship between the mode of tumour cell death (by methods other than PDT) and the efficiency of induction of the immune response, both in vitro and in vivo 36,37 . Although some reports show that apoptotic tumour cells are more effective than necrotic tumour cells at inducing an immune response 38,39 , there are other reports that show that modes of cancer therapy that predominantly induce necrosis are actually better at activating the immune system than methods that predominantly induce apoptosis 40,41 .…”

“…There is an extensive body of literature that examines the pathways of apoptosis that are induced after PDT in both normal and tumour cells in tissue culture, such as signalling pathways 30,31 , mitochondrial events 4 and mediators of apoptosis 32 . The occurrence of apoptosis after PDT in tumours in vivo has also been shown [33][34][35] , but there have been no studies looking at in vivo clearance mechanisms of apoptotic cells in tumours after PDT.Many studies have examined the relationship between the mode of tumour cell death (by methods other than PDT) and the efficiency of induction of the immune response, both in 36,37 . Although some reports show that apoptotic tumour cells are more effective than necrotic tumour cells at inducing an immune response 38,39 , there are other reports that show that modes of cancer therapy that predominantly induce necrosis are actually better at activating the immune system than methods that predominantly induce apoptosis 40,41 .…”

PolyI:C–Induced, TLR3/RIP3-Dependent Necroptosis Backs Up Immune Effector–Mediated Tumor Elimination In Vivo

“…Although necrotic cells prepared by freeze-thaw cycles, formaldehyde fixation, or osmotic shock provoke no protective immune response in a tumor vaccination model (35)(36)(37), heat-killed necrotic cells stimulate antigen-presenting cells to increase production of IL12 and TNFa (38). The inconsistent results among studies might be explained by the differences in the composition and properties of damage-associated molecular patterns (DAMP)-containing RNA released from necrotic cells that depends on type of stimulation, resulting in induction of diverse immune responses.…”