Abstract

Simple SummaryThe genetic adaptability of malignant cells and their consequent heterogeneity even within the same patient poses a great obstacle to cancer patient treatment. This review summarizes the data obtained in the last decade on different preclinical mice models as well as on various immunotherapeutic clinical trials in distinct solid and hematopoietic cancers on how the immune system can be implemented in tumor therapy. Moreover, the different intrinsic and extrinsic escape strategies utilized by the tumor to avoid elimination by the immune system are recapitulated together with the different approaches proposed to overcome them in order to succeed and/or to enhance therapy efficacy.Immune therapy approaches such as checkpoint inhibitors or adoptive cell therapy represent promising therapeutic options for cancer patients, but their efficacy is still limited, since patients frequently develop innate or acquired resistances to these therapies. Thus, one major goal is to increase the efficiency of immunotherapies by overcoming tumor-induced immune suppression, which then allows for immune-mediated tumor clearance. Innate resistance to immunotherapies could be caused by a low immunogenicity of the tumor itself as well as an immune suppressive microenvironment composed of cellular, physical, or soluble factors leading to escape from immune surveillance and disease progression. So far, a number of strategies causing resistance to immunotherapy have been described in various clinical trials, which broadly overlap with the immunoediting processes of cancers. This review summarizes the novel insights in the development of resistances to immune therapy as well as different approaches that could be employed to overcome them.

Highlights

  • It has been demonstrated that the immune system can recognize and, in some cases, successfully eliminate malignant cells, a concept that led to the development of different strategies in tumor immunotherapy ranging from vaccination and adoptive cell therapy (ACT) to the use of immune checkpoint inhibitors

  • After introducing the key mechanisms of immune cell recognition of tumor cells and the major immunotherapeutic options utilized, this review summarizes the different strategies employed by transformed cells to avoid immune recognition and delineates various approaches to overcome such resistances that are currently tested in preclinical mouse models as well as in clinical trials

  • Tumor epitopes that are recognized by CD8+ T cells can be classified in tumor-specific antigens (TSA), which are only expressed in tumors due to mutations or fusions resulting from chromosomal translocation and tumor-associated antigens (TAA), expressed by healthy cells but in altered amounts or locations such as cancer testis antigens, differentiation antigens, or viral antigens

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Summary

Introduction

It has been demonstrated that the immune system can recognize and, in some cases, successfully eliminate malignant cells, a concept that led to the development of different strategies in tumor immunotherapy ranging from vaccination and adoptive cell therapy (ACT) to the use of immune checkpoint inhibitors (iCPI). Due to their genetic instability, transformed cells are highly adaptable and can acquire, either spontaneously or under the selective pressure of an ongoing immune response, different characteristics that allow them to avoid such recognition or even to actively suppress a productive immune response leading to tumor progression and/or relapse. After introducing the key mechanisms of immune cell recognition of tumor cells and the major immunotherapeutic options utilized, this review summarizes the different strategies employed by transformed cells to avoid immune recognition and delineates various approaches to overcome such resistances that are currently tested in preclinical mouse models as well as in clinical trials

How the Immune System Can Recognize Malignant Cells
Immunotherapeutic Approaches
Mechanism of Tumor Resistance
Avoiding Recognition
Direct Inhibition via Upregulation of iCP and Their Inhibitory Ligands
Recruitment of Immune Suppressive Cells
Establishment of a Suppressive TME
Conclusions
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