Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination

Abstract

Using a model of established malignancy, we found that cyclophosphamide (Cy), administered at a dose not requiring hematopoietic stem cell support, is superior to low-dose total body irradiation in augmenting antitumor immunity. We observed that Cy administration resulted in expansion of tumor antigen-specific T cells and transient depletion of CD4+Foxp3+ regulatory T cells (Tregs). The antitumor efficacy of Cy was not improved by administration of anti-CD25 monoclonal antibody given to induce more profound Treg depletion. We found that Cy, through its myelosuppressive action, induced rebound myelopoiesis and perturbed dendritic cell (DC) homeostasis. The resulting DC turnover led to the emergence of tumor-infiltrating DCs that secreted more IL-12 and less IL-10 compared to those from untreated tumor-bearing animals. These newly recruited DCs, originating from proliferating early DC progenitors, were fully capable of priming T cell responses and ineffective in inducing expansion of Tregs. Together, our results show that Cy-mediated antitumor effects extend beyond the well-documented cytotoxicity and lymphodepletion and include resetting the DC homeostasis, thus providing an excellent platform for integration with other immunotherapeutic strategies.

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

“…For example, it has been reported that CTX and 5-FU are less damaging for most primitive cells than other cytotoxic drugs. 118 Furthermore, although high-dose CTX kills BM-resident DC precursors, thus hampering DC mobilization at the peripheral level, 119,120 these precursors are resistant to low-dose CTX, which instead boosts the differentiation of mature DCs in vivo and ex vivo. 21,121,122 Of note, CTX-induced mobilization and maturation of DCs from their BM precursors was mediated by endogenous type I IFN.…”

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

“…Further attempts to prolong Treg depletion have yielded no additional benefit. 66 It is generally believed that the antitumor immunity induced by the combination of chemotherapy and immunotherapy depends on the homeostatic role of immunotherapy acting during the recovery phase that follows the chemotherapy mediated myelolymphodepletion. 67 The ability of this drug to reverse the systemic and in situ DC paralysis in tumor-bearing hosts and its ability to mobilize early proliferating DC progenitors are other crucial mechanisms for enhancing antitumor immunity.…”

“…67 The ability of this drug to reverse the systemic and in situ DC paralysis in tumor-bearing hosts and its ability to mobilize early proliferating DC progenitors are other crucial mechanisms for enhancing antitumor immunity. 66 In this aspect, it was observed that CTX administration restores myelopoiesis, leading to reversion of systemic and in situ tumor-induced DC paralysis. Moreover, CTX mobilized proliferating early DC progenitors to the tumor site where they yielded new DCs.…”

“…These precursor cells proliferate rapidly on the periphery and increase the presence of new APCs that can prime de novo T cell responses. 66 Thus, CTX has a direct impact on DC-T cell interactions in a tumor-bearing host that ultimately lead to a better priming of tumor-specific T cells. These observations support the notion that mobilization of early DC precursors to sites of ongoing immune response and their differentiation into mature DCs can lead to optimal T cell priming.…”

“…68,69 Therefore, CTX can influence the DC homeostasis both in situ and systemically through its unique ability to mobilize DC precursors. 66 Another important finding on the immune effects of CTX was that a single administration of low-dose CTX (50 mg/kg) in tumor-bearing mice prior to immunization with DC increases the frequency of IFN-c secreting antitumor CTLs. 61 This is in agreement with the fact that different chemotherapeutic agents at very low concentrations increase the ability of DCs to induce T cell proliferation.…”