Chemotherapy‐induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death

Abstract

Certain chemotherapeutic regimens trigger cancer cell death while inducing dendritic cell maturation and subsequent immune responses. However, chemotherapy-induced immunogenic cell death (ICD) has thus far been restricted to select agents. In contrast, several chemotherapeutic drugs modulate antitumor immune responses, despite not inducing classic ICD. In addition, in many cases tumor cells do not die after treatment. Here, using docetaxel, one of the most widely used cancer chemotherapeutic agents, as a model, we examined phenotypic and functional consequences of tumor cells that do not die from immunogenic cell death. Docetaxel treatment of tumor cells did not induce ATP or HMGB1 secretion, or cell death. However, calreticulin exposure was observed in all cell lines examined after chemotherapy treatment. Killing by CEA, MUC-1, or PSA-specific CD8+ CTLs was significantly enhanced after docetaxel treatment. This killing was associated with increases in components of antigen-processing machinery, and mediated largely by calreticulin membrane translocation, as determined by functional knockdown of calreticulin, PERK, or calreticulin-blocking peptide. A docetaxel-resistant cell line was selected (MDR-1+, CD133+) by continuous exposure to docetaxel. These cells, while resistant to direct cytostatic effects of docetaxel, were not resistant to the chemomodulatory effects that resulted in enhancement of CTL killing. Here, we provide an operational definition of “immunogenic modulation,” where exposure of tumor cells to nonlethal/sublethal doses of chemotherapy alters tumor phenotype to render the tumor more sensitive to CTL killing. These observations are distinct and complementary to immunogenic cell death and highlight a mechanism whereby chemotherapy can be used in combination with immunotherapy.

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

“…4,5,28,29 In our study, we found that the release of HSP70 and HMGB1 into CRC cell supernatants was significantly increased after OXA and/or 5-Fu treatment. Additionally, HSP70 and HMGB1 concentrations in the supernatants of cells treated with the combination of OXA and 5-Fu were even higher than after treatment with OXA or 5-Fu alone.…”

“…32 In addition to the putative role of HMGB1 in the promotion of tumor progression, certain preclinical and clinical data have revealed that HMGB1 seems to induce the functional maturation of DCs and to trigger protective anti-cancer T cell responses. 4,5,16,20 The question of how DCs decode DAMPs needs to be further investigated. Recent studies have highlighted that after treatment with chemotherapeutic drugs, apoptotic tumor cells can release microparticles, which may contain DAMPs that stimulate DCs and can be used to effectively kill tumor cells.…”

“…In the TLR4-antagonist group, 30 mg/ml HTA125 (HBT, Uden, The Netherlands), an anti-TLR4 monoclonal antibody, was administered before stimulation with untreated CTR-sup, OXA-sup, 5-Fusup or OXA15-Fu-sup. 26 Human DCs (2310 5 ) and autologous peripheral blood lymphocytes (2310 6 ) or BMDCs (2310 5 ) and autologous splenocytes (2310 6 ) from WT or TLR4 2/2 C57BL/6 mice were cocultured in 1 ml RPMI 1640 medium supplemented with 10% fetal calf serum in 24-well plates. The human peripheral blood lymphocytes or mouse splenocytes were restimulated with autologous fresh supernatant-pulsed DCs every 7 day for three times respectively.…”

“…Through experiments performed in vivo and in vitro, DAMPs induced by chemical drugs have been demonstrated to stimulate dendritic cells (DCs) to induce an anti-cancer immune response. [3][4][5] However, DAMPs also play a putative role in the promotion of tumor progression by attracting immature myeloid cells and triggering tumor cell proliferation. [6][7][8] Thus, how to more efficiently trigger an anti-cancer immune response mediated by DAMPs is worthy of attention.…”

Anti-tumor immunity of BAM-SiPc-mediated vascular photodynamic therapy in a BALB/c mouse model

“…More importantly, this CRT signal was detected on the tumor cell surface (Figure 2d). Because CRT can bind to damaged cells and CRT-associated tumor cells are more susceptible to cytotoxic lymphocyte attack, 7,19,54,55 results of immunostimulatory chemotherapy using anthracyclines and with the presumed role of surface CRT as an "eatme" signal on the stressed cells. 56,57 VPDT-mediated anti-tumor immunity relies heavily on the activity of T cells.…”