Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice

Abstract

Cancer immunotherapy faces a serious challenge because of low clinical efficacy. Recently, a number of clinical studies have reported the serendipitous finding of high rates of objective clinical response when cancer vaccines are combined with chemotherapy in patients with different types of cancers. However, the mechanism of this phenomenon remains unclear. Here, we tested in mice several cancer vaccines and an adoptive T cell transfer approach to cancer immunotherapy in combination with several widely used chemotherapeutic drugs. We found that chemotherapy made tumor cells more susceptible to the cytotoxic effect of CTLs through a dramatic perforin-independent increase in permeability to GrzB released by the CTLs. This effect was mediated via upregulation of mannose-6-phosphate receptors on the surface of tumor cells and was observed in mouse and human cells. When combined with chemotherapy, CTLs raised against specific antigens were able to induce apoptosis in neighboring tumor cells that did not express those antigens. These data suggest that small numbers of CTLs could mediate a potent antitumor effect when combined with chemotherapy. In addition, these results provide a strong rationale for combining these modalities for the treatment of patients with advanced cancers.

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…109 Paclitaxel, cisplatin and doxorubicin sensitize tumor cells to CTLs by rendering them permeable to granzyme B via upregulation of mannose-6-phosphate receptors on tumor cell surface. 110 Furthermore, CTX sensitizes tumor cells to TRAIL-dependent CD8 T-cellmediated immune attack, 111 suggesting that TRAIL-mediated tumor cell killing contributes to immunogenic TCD. 112 Platinum derivatives and dacarbazine were shown to stimulate the expression of ligands for NKG2D, an NK cellactivating receptor, resulting in augmented NK-cell cytotoxicity and IFN-g production.…”

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…Although 16 of 48 patients discontinued the trial because of adverse effects (AEs) and 4 fatalities occurred, treatment with nivolumab 3 mg/kg with ipilimumab 1 mg/kg achieved a higher objective response rate (ORR) regardless of histology type (29%). At 2016 ASCO, 14,20 77 patients randomly assigned into 2 cohorts either received nivolumab 3 mg/kg q2w with ipilimumab 1 mg/kg every 12 weeks or 6 weeks (38 and 39 patients, respectively). The results showed that patients in the ipilimumab every 12 weeks cohort seemed to have better response to treatment with prolonged median progression-free survival (PFS: 8.1 vs. 3.9 months).…”

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

“…100 This finding was reinforced by other authors who have observed that the in vitro treatment of murine colon cancer cells with low concentrations of PTX or doxorubicin increased their sensitivity to specific anti-p53 CTL. 80 Authors obtained similar results treating human lung cancer cells (H332). Although no direct effect of PTX on murine lymphocytes was observed, doxorubicin negatively affected cell toxicity 80 and human peripheral blood cells were sensitive to drug treatment.…”

“…Similar results were observed in the tumor progression of a breast cancer model, which growth was delayed in contrast with the poor activity of drug alone. 80 Immunotherapy based on the administration of cytokines is one of the goals of several groups. It was observed, for instance, that the incubation of tumor cells with granulocytemacrophage colony-stimulating factor (GM-CSF) induces cell surface modification.…”

“…Such enhanced sensitivity of tumor cells to CTL cytotoxicity was attributed to the ability of PTX, doxorubicin and cisplatin to increase the cell permeability to Granzyme B. 80 The dying tumor cells can release danger signals (damageassociated molecular pattern, DAMP) that lead to the activation of DCs and may facilitate the engulfing and processing of tumor antigens 101,102 ; however, it is usually supposed that massive tumor cell death or apoptosis is nonimmunogenic.…”