Cyclophosphamide enhances immunity by modulating the balance of dendritic cell subsets in lymphoid organs

Abstract

Cyclophosphamide (CTX), a commonly used chemotherapeutic agent can enhance immune responses. The ability of CTX to promote the proliferation of effector T cells and abrogate the function of regulatory T cells (Tregs) has been described. In this study, we examined the effects of CTX treatment on dendritic cell (DC) subsets and the subsequent outcome on the effector and suppressive arms of adaptive immunity. In secondary lymphoid tissues, tissue-derived migratory DCs (migratory DCs), lymphoid tissueresident DCs (resident DCs), and plasmacytoid DCs (pDCs) are well described. CTX has profound and selective cytotoxic effects on CD8 ؉ resident DCs, but not skin-derived migratory DCs or pDCs in lymph nodes (LNs) and spleen, causing an imbalance among these DC subsets. CTX treatment increases the potency of IntroductionCyclophosphamide (CTX) is a chemotherapeutic agent, which is used for the treatment of leukemias, lymphomas, and solid tumors. [1][2] In recent years, in part because of the challenges of stimulating effective immunity in the tumor-bearing host, the immunomodulatory effects of CTX have become an area of interest. Dose-dependent effects of CTX on the secretion of type I interferons (IFNs), homeostatic proliferation, and on depleting regulatory T cells (Tregs) have been proposed as mechanisms for the observed enhancement in immune responses. 2-10 CD4 ϩ CD25 ϩ Tregs are very sensitive to CTX, and exhibit increased levels of apoptosis and decreased ability to suppress T-cell proliferation in vitro after CTX treatment. [11][12][13] A role for CTX in improving dendritic cell (DC) function has also been proposed. 14 Recently, feedback control of regulatory T-cell homeostasis by DCs has been demonstrated in vivo, suggesting that therapeutic modulation of DCs could also lead to altered Treg function. 15 Although immune responses are modified by the interplay among DCs, effector T cells, and Tregs, 16 the effects of CTX on specific DC subsets has not been investigated.DCs are specialized antigen-presenting cells that are critical in both initiating immunity to pathogens and promoting tolerance to self. 17 DCs can be divided into 2 main categories: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs can be further divided into 2 main subsets: tissue-derived migratory DCs (migratory DCs) and lymphoid tissue-resident DCs (resident DCs). Migratory DCs access the local draining lymph nodes (LNs) from residing peripheral tissues, whereas resident DCs are replenished by blood-borne precursors from the bone marrow. 18 Thus, resident DCs are found in lymph nodes (LNs) and spleen, but migratory DCs are found only in LNs. Resident DCs can be further subdivided into 3 types: CD8 ϩ DCs, CD4 ϩ DCs, and CD4 Ϫ CD8 Ϫ DCs. 17 Because migratory DCs can transfer antigens to resident DC subsets and both can present antigens to naive CD8 ϩ and CD4 ϩ T cells, how the balance of DC subsets results in tolerance to self or reactivity to pathogens is not known. 17,19 In this study, we examined the effects of CTX treatment on DC subset...

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

“…CTX exerted its effects preferentially on the CD8a-expressing-DC subset, determining an initial ablation of lymphoid organ-resident CD8a þ DCs, followed by overshoot replenishment after drug discontinuation. 20,21 Data from our laboratory have revealed that, after CTX administration, CD8a þ DCs migrate to the tumor site where they cross-present tumor-associated antigen ( Figure 2). The platinum-based compound cisplatin was also reported to modulate the percentages of myeloid cells by increasing DCs and eliminating myeloid-derived suppressor cells (MDSCs), thus favoring immune effector responses in melanoma-bearing mice.…”

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

“…The cyclophosphamide 20 was purchased from Sigma-Aldrich (St Louis, MO, USA) and dissolved in 0.9% normal saline (NS) according to the manufacturer's instructions. The fluorescein isothiocyanate anti-mouse CD4 monoclonal antibody (mAb) and phycoerythrin anti-mouse CD25 mAb were purchased from eBioscience (San Diego, CA, USA).…”

“…20,40,[42][43][44] In cancer patients, immunotherapy that specifically targets Tregs may fail or be insufficient to reverse tumor growth, depending on the cancer type. The efficacy of an immunotherapy depends upon its ability to effectively overcome immune evasion mechanisms and generate new antitumor responses and/or upregulate the existing responses.…”

“…In recent years, many immunologists have investigated the depletion of Tregs by low-dose cyclophosphamide (CY) 20 in tumors and certain autoimmune conditions. CY, which is a nitrogen mustard compound, is widely used in the treatments of leukemia, lymphomas and solid tumors, and exhibits effective cytotoxicity against tumor cells.…”

Gemcitabine enhances antitumor efficacy of recombinant lipoimmunogen-based immunotherapy

“…7,8 Recently, accumulating evidence revealed that antigen processing and presentation by dendritic cells (DCs) were enhanced by certain chemotherapeutic drugs administered at low doses. [9][10][11] Anticancer drugs also have been shown to possess adjuvant activity to stimulate tumor-specific immune responses via the accumulation of DCs at the tumor site and the activation of antigen-specific CTLs during cancer immunotherapy. 12 Moreover, several clinical reports indicated that the combination of immunotherapy with chemotherapeutic agents led to considerable improvement in the survival rate of patients with cancer.…”