Elsevier

Cellular Immunology

Volume 343, September 2019, 103730
Cellular Immunology

Research paper
The tumor microenvironment: Thousand obstacles for effector T cells

https://doi.org/10.1016/j.cellimm.2017.12.004Get rights and content

Highlights

  • Tumor infiltrating T cells over express immune check point receptors.

  • Clinical usage of check point inhibitors improve patients outcome.

  • Tumor cells induce immune suppressive properties of immune and stromal cells.

  • Tumor cell metabolism alter the microenvironment influencing T cell functions.

  • Identification of biomarkers is required to optimize personalized immune therapy.

Abstract

The immune system is endowed with the capability to recognize and destroy transformed cells, but even in the presence of an immune infiltrate many tumors do progress. In the last decades new discoveries have shed light into (some of) the underlying mechanisms. Immune effector cells are not only under the influence of immune suppressive cell subsets, but also intrinsically regulated by immune check point molecules that under physiological condition avoid attach of healthy tissue. Moreover, tumor cells are modifying the surrounding microenvironment through secretion of immune modulators as well as via their own metabolism, thus further impairing the development of immune effector functions. Different approaches are currently being evaluated in the clinic to overcome those regulatory mechanisms and to unleash effector T cells.

Introduction

Since the demonstration that T cells can recognize tumor associated antigens (TAA), which lead to the eradication of cancer cells, efforts have been made to increase the understanding of the interaction between T cells and tumor cells and to improve the use of this knowledge not only to enhance the ability to cure cancer patients with novel immune based therapies, but also to select the best therapy for each tumor patient.

During the last two decades different strategies have been identified through which tumor cells can protect themselves against antigen specific CD8+ cytotoxic T lymphocytes (CTLs). Some of them are “normal” negative feedback mechanisms of the immune system, which are required under physiologic conditions to shut down a successful immune response in order to avoid damage to bystander healthy tissues. These include the induction of negative regulators on the effector cells to inhibit their response, but also the recruitment/polarization of immune suppressive cells. In addition, the tumor is converting the microenvironment into a hostile environment for T cells and their ability to perform effector functions, which is related to the tumor metabolism that not only deplete important nutrients for the T cells, but also induce accumulation of “waste products”, which could further impair T cell function.

In the following sections we will discuss in more detail all these distinct mechanisms summarized in Fig. 1 and the implementation of this information to improve immunotherapeutic strategies in preclinical experimental models and in the clinic (Fig. 2).

Section snippets

Immune check point as an intrinsic shut down mechanism

In order to keep a balance between the elimination of dangerous entities and protection of healthy tissues, different negative feedback mechanisms exist in the immune system. Thus, directly after recognizing their target structure and performing their effector activity, T cells upregulate one or more negative feedback process(es) leading to a shut-down of the response, once the danger is eliminated. The prototype of this mechanism encompass immune check point (ICP) molecules or co-inhibitory

Co-stimulatory molecules

Comparison of the phenotype of Teffs and Tregs from TILs and peripheral blood mononuclear cells (PBMNCs) as well as from cancer patients and healthy donors highlights low levels of co-stimulatory molecules on effector cells, whereas higher levels are found on Tregs [59]. Since in most cases triggering of the co-stimulatory molecule on Tregs reduces their suppressive activity and/or induces their depletion, different clinical attempts are utilizing agonists of such co-stimulatory molecules to

Immune suppressive cells

Tumor cells are able to subvert immune cells and to polarize them toward tumor-promoting and/or immune suppressing types. In addition, cellular components of the tumor microenvironment (TME), like tumor associated fibroblasts (TAFs), endothelial cells (ECs) and tumor associated neutrophils (TANs) can be manipulated by the tumor for protection against an immune response.

Ostile microenvironment

In addition to the above mentioned immune mechanisms, also other “general” aspects of the TME modulate the composition of the tumor infiltrating immune cell repertoire as well as the activity of immune cells.

Clinical translation

Against all the above described mechanisms of immune evasion exploited by the cancer, different attempts to overcome them therapeutically have been undertaken (Fig. 2). As stated above, therapy with CPIs has provided some good responses, but only in 20–40% of patients and some of them develop resistances during treatment [146], [147], [148]. Therefore the search for criteria to stratify patients (see below), but also to develop even more potent treatment options are urgently required. Recently,

The quest for the holy grail: immune markers with prognostic and/or predictive value

The above data demonstrate that just the presence of an immune cell infiltrate cannot be a sufficient marker for cancer patients. For that reason many laboratories have taken/are undergoing the difficult task of identifying biomarkers correlated with disease progression and patients’ survival, both spontaneous (i.e. prognostic markers) and in response to therapy (i.e. predictive markers), in order to stratify patients accordingly and thus being able to perform a personalized therapy, selecting

Conclusion

In the last decade a greater understanding of the interaction between tumor and immune cells has been obtained and its translation into clinical practice has resulted in some great clinical responses. Despite this improvement, a long way has still to be undertaken in order to expand the patients that can really take advantages from such therapies, both by enhancing their efficacy and by finding reliable markers to initially select the best therapy for each patient and for monitoring the

Acknowledgment

The work was supported by a grant the Mildred Scheel Stiftung to CM and BS (111105).

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