Table 7.
Existence of intrinsic or naturally occurring resistance to ICD in experimental cancer models.
| ICD inducer(s) | Experimental set-up where resistance was observed | Reason behind resistance | Rescued by? | Clinical applicability verified? | Reference |
|---|---|---|---|---|---|
| In vivo preclinical setting (cancer cell or host immune system-level resistance) | |||||
| Anthracyclines or anthracycline plus oxaliplatin | C3H mice with naturally occurring tlr4 mutation | Host immune system-level resistance: defective TLR4 in C3H mice causes failure of HMGB1-mediated immunity thereby leading to resistance to anti-cancer vaccination effect associated with anthracyclines treatment | Adoptive transfer of TLR4-expressing DCs loaded with dying tumor cells | Yes; breast cancer, colon cancer, and lung cancer patients carrying TLR4 gene mutation that ablates its ability to bind its ligands is associated with worse prognosis post-treatment | (215) |
| Doxorubicin | AT-3 or 4T1.2 breast cancer cells in C57BL/6 or BALB/c mice, respectively | Cancer cell-level resistance: CD73 overexpression confers chemo-resistance to doxorubicin by suppressing anti-tumor immunity through A2A adenosine receptors | Blockade of CD73 | Yes; in triple-negative breast cancer patients, high CD73 in anthracycline-treatment set-up associated with lower rate of complete responses | (216) |
| Mitoxantrone and Hypericin-PDT | AY27 rat bladder cancer cells in Fischer 344 rats | Cancer cell-level resistance: low endogenous CRT levels, resulted in severely reduced surface-CRT upon treatment with mitoxantrone or Hyp-PDT; this in turn compromised immunogenic phagocytic clearance and anti-cancer vaccination effect | Exogenous addition of recombinant CRT | Yes; high tumoral CALR levels correlated with high expression of phagocytosis-associated genes and predicted for prolonged survival after RT or PTX treatment of lung or ovarian cancer patients respectively | (42) |
| Oxaliplatin | Autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model of metastatic prostate cancer | Host immune system-level resistance: immunosuppressive B cells expressing IgA, IL10 and PD-L1 cause resistance to anti-tumorigenic effects of oxaliplatin | Genetic or pharmacological depletion of B cells | Not directly, but possible validity is supported by human patient data showing that IL-10 expressing IgA+ cells are abundant in therapy-resistant prostate cancer and are negative prognostic indicators | (217) |
| In vitro preclinical setting (cancer cell-level resistance) | |||||
| Anthracycline | SH-SY5Y neuroblastoma cell line | Anthracycline treatment of these cells failed to induce surface-CRT due to reduced capacity to efflux ER-Ca2+ into cytosol | Overexpression of reticulon-1C | – | (132) |
| Doxorubicin | HT29-dx and HT29 iNOS-cells (human colon cancer cells) | Doxorubicin failed to induce NO synthesis, which resulted in reduced toxicity, reduced surface-CRT and subsequently compromised immunogenic phagocytic clearance and DC stimulation | Addition of sodium nitroprusside or a NO donor | – | (218) |
| Doxorubicin | MDR+ human cancer cells (HT29-dx, A549-dx and MCF-7-dx) | Increased MDR levels caused increased P-glycoprotein expression which caused resistance to doxorubicin-induced ICD by affecting immunogenic phagocytic removal | Addition of zoledronic acid | Not directly | (219) |
CD, cluster of differentiation; CRT or CALR, calreticulin; DC, dendritic cells; ER, endoplasmic reticulum; HMGB1, high-mobility group box-1 protein; HSP, heat shock protein; Hyp-PDT, hypericin-photodynamic therapy; ICD, immunogenic cell death; IL, interleukin; MDR, multiple drug-resistance; NO, nitric oxide; NOS, nitric oxide synthase; PD-L1, programed cell death protein ligand 1; PTX, paclitaxel; RT, radiotherapy; TLR, toll-like receptor.