Cancer Letters

Cancer Letters

Volume 370, Issue 1, 1 January 2016, Pages 85-90
Cancer Letters

Mini-review
Immunotherapy and tumor microenvironment

https://doi.org/10.1016/j.canlet.2015.10.009Get rights and content

Highlights

  • The TME can dampen or enhance the efficacy of immunotherapy.

  • Immunotherapy targets both the TME and tumor cells.

  • Manipulating the TME can improve current immunotherapies.

Abstract

Recent exciting progress in cancer immunotherapy has ushered in a new era of cancer treatment. Immunotherapy can elicit unprecedented durable responses in advanced cancer patients that are much greater than conventional chemotherapy. However, such responses only occur in a relatively small fraction of patients. A positive response to immunotherapy usually relies on dynamic interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). Depending on the context of these interactions, the TME may play important roles to either dampen or enhance immune responses. Understanding the interactions between immunotherapy and the TME is not only critical to dissect the mechanisms of action but also important to provide new approaches in improving the efficiency of current immunotherapies. In this review, we will highlight recent work on how the TME can influence the efficacy of immunotherapy as well as how manipulating the TME can improve current immunotherapy regimens in some cases.

Introduction

Led by immune checkpoint inhibitor and chimeric antigen receptor (CAR) T cell therapies, cancer immunotherapy has shown remarkable long-term efficacy in patients with a variety of cancers [1], [2], [3], [4]. Conventional therapies for cancers, such as radiation and chemotherapy, usually target the tumor cells themselves and can induce positive responses in the majority of patients. Despite initial responses to these conventional therapies, relapse and resistance often occur in patients with advanced cancer after prolonged treatment [5]. In significant contrast to conventional therapies, immunotherapy targets the immune system to provoke a systemic response against tumors. Clinical trials with immune checkpoint inhibitors have shown unprecedented durable responses [6], although these positive responses are limited to a small fraction of patients. The top priorities in the immunotherapy field therefore include understanding the mechanisms of action in detail and how we can extend the positive responses to a broader range of patients.

The immune system can recognize tumor antigens and kill tumor cells in vitro [7], [8]. However, recognition of the tumor antigen alone is not sufficient for the host to eradicate established tumors in vivo [9], [10], [11]. An established tumor is a complex tissue composed not only of tumor cells but also of stromal cells, inflammatory cells, vasculature, and extracellular matrices (ECM), all of which are defined together as the tumor microenvironment (TME) [12], [13]. Successful tumor control by immunotherapy requires the activation of the immune system, expansion of the effector cells, infiltration of activated effector cells to the tumor tissue, and destruction of the tumor cells (Fig. 1). However, the TME usually prevents effective lymphocyte priming, reduces its infiltration, and suppresses infiltrating effector cells, which leads to a failure of the host to reject tumors. The mechanisms accounting for the resistance to immunotherapy include the following: 1) an inhibitory microenvironment or lack of antigen stimulation/co-stimulation for immune cells, especially T cells, within the TME that may promote tumor growth and immune escape; 2) biological barriers around tumor tissues that can lead to inadequate numbers of immune cells migrating into tumor sites; 3) exhausted or short-lived activation of antigen-specific T cells with limited repertoires that fail to suppress tumor growth; and 4) poor direct or indirect antigen presentation in lymphoid tissues that lead to a lack of T-cell priming due to insufficient release of tumor antigens to the draining lymph node by the TME. Thus, a better understanding of the interactions between immunotherapy and the TME may provide new approaches to improve the response rates of current immunotherapies. As the contributions of the TME in conventional therapies have recently been reviewed [12], we will focus on the developments in understanding the interactions between immunotherapy and the TME.

Section snippets

Checkpoint blockade antibodies

Immune checkpoints refer to a series of pathways that can regulate T cell activity as either co-inhibitory or co-stimulatory signals [14], and they function to protect the host against autoimmunity under normal conditions [15], [16]. Increasing evidence suggests that tumors use many of these pathways as important mechanisms to escape antitumor immune responses [6], [17], [18]. Among them, inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand, PD-1 ligand (PD-L1 or B7H1),

Conclusions

The immune response is a dynamic and complex process wherein different mechanisms balance each other in order to protect the host, local tissues and cells, including tumor cells from immune destruction. The TME is one location in which both immunosuppressive and immunosupportive mechanisms converge, but suppressive mechanisms usually take over. The recent success of checkpoint blockades is a proof-of-concept showing that manipulating different signaling pathways can create therapeutics that are

Conflict of interest

None.

Acknowledgement

We thank Dr. Mendy Miller for helpful scientific discussions and editing. This study was partially supported by the U.S. National Institutes of Health through National Cancer Institute grants CA141975 and grants from the Chinese Academy of Sciences (XDA09030303) to Yang-Xin Fu. Haidong Tang has been supported by a postdoctoral fellowship from the Cancer Research Institute.

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