Elsevier

Blood Reviews

Volume 32, Issue 6, November 2018, Pages 449-456
Blood Reviews

Review
Recipient and donor cells in the graft-versus-solid tumor effect: It takes two to tango

https://doi.org/10.1016/j.blre.2018.04.002Get rights and content

Abstract

Allogeneic hematopoietic stem cell transplantation (alloHSCT) produces –similar to the long-established graft-versus-leukemia effect– graft-versus-solid-tumor effects. Clinical trials reported response rates of up to 53%, occurring mostly but not invariably in association with full donor chimerism and/or graft-versus-host disease. Although donor-derived T cells are considered the principal effectors of anti-tumor immunity after alloHSCT or donor leukocyte infusion (DLI), growing evidence indicate that recipient-derived immune cells may also contribute. Whereas the role of recipient-derived antigen-presenting cells in eliciting graft-versus-host reactions and priming donor T cells following DLI is well known, resulting inflammatory responses may also break tolerance of recipient effector cells towards the tumor. Additionally, mouse studies indicated that post-transplant recipient leukocyte infusion produces anti-leukemia and anti-solid-tumor effects that were exclusively mediated by recipient-type effector cells, without graft-versus-host disease. Here, we review current preclinical and clinical evidence on graft-versus-solid-tumor effects and growing evidence on the effector role of recipient-derived immune cells in the anti-tumor effect of alloHSCT.

Introduction

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is recognized as one of the most effective strategies in the treatment of advanced hematological cancers, particularly in combination with donor leukocyte infusion (DLI) [[1], [2], [3], [4]]. Whereas treatment with hematopoietic stem cell transplantation was initially conceived to reconstitute the hematopoietic system after high-dose chemo-radiotherapy, soon it became evident that the curative potential of alloHSCT can be attributed to an immune-based response of the transplanted and reconstituting donor cells against the malignant cells, also referred to graft-versus-tumor (GvT) effect [5,6]. Over the last decade, the field of alloHSCT has continued to evolve, with an emerging role for alloHSCT in the treatment of advanced solid tumors [7], and growing evidence on the potential contribution of recipient immune cells in the anti-tumor reactivity following alloHSCT.

Section snippets

AlloHSCT and the existence of a graft-versus-tumor effect

In early alloHSCT regimens, myeloablative conditioning including high-dose chemo-radiotherapy was used to maximally eradicate cancer cells to suppress the recipient immune system and allow donor engraftment. However, such high-dose regimens were associated with high treatment-related toxicities [8] and induction of chemo-resistance [9] while disease recurrence still occurred indicating that high-dose cytotoxic therapy was unable to eliminate tumor cells completely [10]. Moreover, the notion of

AlloHSCT in the treatment of advanced solid tumors

With currently available therapies, several types of advanced-stage solid tumors still present with a bleak prognosis. The observation that GvL effects can produce durable remissions in hematologic cancer patients, led researchers to investigate whether alloHSCT holds potential for solid tumors. Since inflammation was shown to facilitate trafficking of alloreactive T cells from the lymphohematopoietic system into epithelial target cells [24,25], it was postulated that the same mechanism would

A role for recipient immune cells in the anti-tumor effects of alloHSCT

The very first to speculate on a role for recipient immune cells in the anti-tumor effect of donor cell therapy were Alexander et al. in 1966, in a study showing that xenogeneic lymphocytes from tumor-immunized sheep reduced fibrosarcoma growth in immunocompetent rats. The authors postulated that the observed anti-tumor effect was not mediated via direct anti-tumor reactivity of donor T cells as these were rapidly rejected in the xenogeneic setting, but indirectly through what they called a

Conclusion

The finding that alloHSCT can generate immune anti-tumor effects against hematologic as well as solid tumors, is one of the most important advances in the field of HSCT. Although donor T cells are considered the principal mediators of the anti-tumor effect following alloHSCT, recent observations also indicate a key role for recipient-derived immune cells. The presence of recipient APC was shown to be crucial for effective anti-tumor responses as a means to increase the immunocompetence and to

Practice points

  • •

    There is growing preclinical and clinical evidence to indicate that alloHSCT can provide an immune anti-solid tumor effect.

  • •

    Clinical observations indicate that full donor chimerism and GvHD are not prerequisites for effective anti-solid tumor immunity after alloHSCT.

  • •

    Whereas the importance of pre-existing recipient chimerism is well known in anti-tumor responses provided by post-transplant DLI, evidence has emerged indicating that recipient immune cells can also contribute as effectors to the

Research agenda

  • •

    Prospective monitoring of recipient immune cell activation in clinical trials with alloHSCT for advanced solid tumors would contribute to a better understanding of the emerging role of recipient effector cells in the anti-tumor effect.

  • •

    Experimental studies should further unravel the interactions between the different effector immune cells thought to be involved in the anti-solid tumor effect of alloHSCT. Experimental models should be expanded to include other common and difficult-to-treat solid

Conflict of interest statement

The authors declare that they have no conflict of interest.

Funding

Isabelle Dierckx de Casterlé is supported by the Olivia Hendrickx Research Fund (www.Olivia.be). This funding source supported the work to obtain the documented findings on the role of recipient effector cells following post-transplant challenge with RLI in the preclinical neuroblastoma model, but had no involvement in the collection, analysis or interpretation of the data, nor in the writing of the manuscript.

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