Research paperThe tumor microenvironment: Thousand obstacles for 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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