Cancer-Induced Immune Suppression: An Achilles’ Heel of Current Immunotherapy

Dear Colleagues,

The concept of the immune surveillance of cancer is over 100 years old. It was first conceived by Paul Erlich, a Nobel-Prize-winning German physician who suggested that immune cells are endowed with a remarkable ability to recognize, target, seek, and destroy malignant cells. Erlich noted that the incidence of cancer would be considerably higher in the absence of these vigilant immune cells. It took decades for the scientific community to accept the existence of immune surveillance and to recognize that it was deficient or absent in most patients with cancer—especially those with advanced disease. Extensive phenotypic and functional analyses of tumor-infiltrating immune cells (TILs) in a variety of human tumor types indicated that TILs were functionally deficient and only regained the capability to mediate anti-tumor cytotoxicity after their removal from the TME. The notion that progressing tumors actively suppressed immune cells in the TME finally gained widespread attention approximately 15 years ago and has led to a flurry of mechanistic studies aimed at establishing the molecular underpinning of TIL immune dysfunction. These studies culminated in the discovery of PD-1/PD-L1 checkpoint inhibition and subsequent translation to the clinic of antibody-mediated blockade of this immune checkpoint. An unprecedented success of the immune checkpoint blockade (ICB) in patients with immune-cell-infiltrated (“hot”) tumors and its relative lack of therapeutic effects in patients with poorly-infiltrated (“cold”) tumors has once again called attention to the intimate relationship between the tumor and immune cells in the TME. It has become clear that human tumors utilize numerous and diverse strategies to escape from the host immune system. In addition to PD-1/PD-L1, other checkpoint inhibitory pathways operate in tumors, and various levels and flavors of suppression are uniquely associated with individual tumors and may determine therapeutic outcomes. Today, with more than 5 years of immune-oncology experience in the clinic, cancer-induced immune suppression is being acknowledged as a major barrier to successful cancer immunotherapy.

With increasing interest in the role tumor-induced immune suppression plays in immunotherapy outcome, it becomes critical to gather and review information available about the capability of tumors to interfere with the host immune system. Such knowledge could serve as a basis for the rational design of future clinical strategies. Moreover, there appear to be several interesting aspects of tumor-induced immune suppression that require attention: (a) it targets a variety of immune cell types; (b) it appears to favor activated immune cells; (c) it interferes with local and systemic immunity; (d) it engages a variety of established cellular mechanisms or pathways; (e) it selectively inhibits anti-tumor effector functions but does not lead to generalized immunodeficiency; and (f) it is closely related to tumor aggressiveness and progression. The mechanism or a sum of mechanisms underlying these various tumor-driven immune effects remains unknown. In this Special Issue, we will attempt to show why and how human tumors mange to create such remarkably powerful and highly personalized inhibitory environments. We will also discuss the potential for overcoming tumor-induced immune suppression by personalized approaches, where therapies could be selected and matched with the prevailing suppressive mechanisms for optimal therapeutic effects. Our major goal will be to convey the notion that a complete understanding of the nature of existing tumor-induced immune suppression in every cancer patient is achievable today and is necessary for the restoration of vigorous and effective anti-tumor immune responses.

Prof. Theresa L. Whiteside
Guest Editor

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