Elsevier

Cellular Immunology

Volume 361, March 2021, 104277
Cellular Immunology

Research paper
Reactive myelopoiesis and the onset of myeloid-mediated immune suppression: Implications for adoptive cell therapy

https://doi.org/10.1016/j.cellimm.2020.104277Get rights and content

Highlights

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    The impact of MDSCs on adoptive T cell therapy is reviewed.

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    Reactive myelopoiesis is driven by lymphodepleting regimens.

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    Strategies to inhibit lymphodepletion-generated MDSCs are discussed.

Abstract

Adoptive T cell therapy (ACT) in combination with lymphodepleting chemotherapy is an effective strategy to induce the eradication of cancer, providing long-term regressions in patients. However, only a minority of patients that receive ACT with tumor-specific T cells exhibit durable benefit. Thus, there is an urgent need to characterize mechanisms of resistance and define strategies to alleviate immunosuppression in the context of ACT in cancer. This article reviews the importance of lymphodepleting regimens in promoting the optimal engraftment and expansion of T cells in hosts after adoptive transfer. In addition, we discuss the role of concomitant immunosuppression and the accumulation of myeloid derived suppressor cells (MDSCs) during immune recovery after lymphodepleting regimens and mobilization regimens.

Introduction

In recent years, there has been an explosion of clinical trials launched to explore the safety and efficacy of ACT for treatment in various malignancies. According to clinicaltrials.gov, more than 300 clinical trials utilizing treatment with lymphodepleting chemotherapies that include cyclophosphamide in combination with ACT are actively recruiting patients. While, preparative lymphodepleting methods are essential to promote the engraftment of adoptively transferred T cells and augment their anti-tumor activity, the concomitant recovery of the endogenous immune system after lymphodepleting regimens can have a profound impact on the function of adoptively transferred T cells. The use of lymphodepleting regimens applies significant pressure on the bone marrow to reconstitute the immune system, which ultimately results in an increased abundance of immunosuppressive myeloid cells. This striking phenomenon is due in part to the mobilization of hematopoietic stem and progenitor cells (HSPCs) from the bone marrow and their differentiation into myeloid cells. The hematopoietic differentiation trajectory and the function of the immune system are hijacked by tumors to promote a growth advantage and evade immune clearance. A variety of factors contribute to the expansion of myeloid cells during stress-induced myelopoiesis which can influence the onset of myeloid-mediated immunosuppression. Tumors preferentially promote the expansion of myeloid cells with potent immunosuppressive functions, including myeloid derived suppressor cells (MDSCs). However, cancer-driven myelopoiesis may differ in the setting of ACT.

In this review, we provide an overview of the known literature pertaining to lymphodepleting regimens that precede ACT. We highlight the resulting accumulation of immunosuppressive myeloid cells which can have profoundly negative consequences on the anti-tumor activity elicited by adoptively transferred T cells. We draw parallels between the known mechanisms that drive myelopoiesis in the presence of pathogenic stimuli or mobilizing cytokines which may also promote the accumulation of myeloid cells in reaction to the stimuli provided by various cytotoxic, lymphodepleting agents. Finally, we provide rationale for strategies to target reactive myelopoiesis with a goal of enhancing therapeutic outcomes for the treatment of cancer with ACT.

Section snippets

Preparative lymphodepletion is essential to elicit durable therapeutic responses to ACT

For nearly 30 years, the infusion of T cells possessing the capability of recognizing and eliminating tumor cells has been explored in patients with cancer. Early studies pioneered by the Rosenberg group at the National Cancer Institute demonstrated that the administration of IL-2 could expand T cells in vivo, leading to durable regressions in patients with metastatic melanoma [1], [2]. This groundbreaking discovery was early evidence that therapies targeting the immune system, but not tumor

Reactive myelopoiesis promotes the expansion of MDSCs

Some of the earliest descriptions of MDSCs in mice and in human subjects were in the context of treatment regimens that included cytokine mobilization or the use of cytotoxic agents, including cyclophosphamide or TBI [29], [30], [31], [32]. The immunosuppressive cells that were described in these studies were broadly characterized as suppressor cells from lymphoid organs after treatment with cyclophosphamide or resembled HSPCs in patients with head and neck cancer [30], [31]. Later studies

The heterogeneity of myeloid cell expansion during reactive myelopoiesis

PMN-MDSCs and M-MDSCs have been shown to be genetically and functionally distinct from physiologic neutrophils and monocytes [72], [73], [74]. Generally, MDSCs have been described to be immunosuppressive, while neutrophils and monocytes from healthy donors or matched hosts do not have an immunosuppressive capacity [72], [74], [75]. However, neutrophils that expand after G-CSF-induced mobilization are phenotypically immature, have a defective chemotactic ability, and exhibit a reduced phagocytic

Factors that drive reactive myelopoiesis in ACT: Opportunity for therapeutic targets?

Indeed, lymphodepleting regimens can deplete immunosuppressive regulatory T cells (Tregs) and MDSCs, but have disparate effects on immune cell reconstitution [101], [102], [103]. Tregs appear to be more sensitive to TBI in comparison to Cy/Flu-based lymphodepletion regimens [103]. Notably, the kinetics of MDSC expansion after lymphodepleting TBI is different than mice treated with chemotherapy. The depletion of MDSCs in TBI-based lymphodepleting regimens is transient and their frequency

The role of danger signals in reactive myelopoiesis

Mounting evidence has highlighted the importance of the microbiota and their products in driving immune responses in cancer [135], [136]. In mice, lymphodepleting doses of cyclophosphamide (i.e. 200 mg/kg body weight in a mouse) can disrupt the gut-epithelial barrier, promoting dysbiosis and the translocation of bacteria from the gut [137]. The efficacy of ACT and effector T cell responses in mice pre-conditioned with cyclophosphamide and antibiotics are reduced in comparison to mice without

Conclusions and future perspectives

Many studies in preclinical models have not included lymphodepleting regimens when studying the anti-tumor effect of adoptively transferred T cells. Indeed, providing an excess of tumor-specific T cells to a tumor-bearing host without any pre-conditioning holds significant value in the investigation of native interactions between cancer and the adaptive immune system. However, the true test of the ability of adoptively transferred T cells to control tumor growth must combine ACT with

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was funded by a Bankhead Coley Cancer Research Grant for the Florida Department of Health.

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