Reactivation of dormant anti-tumor immunity – a clinical perspective of therapeutic immune checkpoint modulation

Abstract

In favor of their outgrowth, cancer cells must resist immune surveillance and edit the immune response. Cancer immunoediting is characterized by fundamental changes in the cellular composition and the inflammatory cytokine profiles in the microenvironment of the primary tumor and metastatic niches, with an ever increasing complexity of interactions between tumor cells and the immune system. Recent data suggest that genetic instability and immunoediting are not necessarily disparate processes. Increasing mutational load may be associated with multiple neoepitopes expressed by the tumor cells and thus increased chances for the immune system to recognize and combat these cells. At the same time the immune system is more and more suppressed and exhausted by this process. Consequently, immune checkpoint modulation may have the potential to be most successful in genetically highly altered and usually extremely unfavorable types of cancer. Moreover, the fact that epitopes recognized by the immune system are preferentially encoded by passenger gene mutations opens windows of synergy in targeting cancer-specific signaling pathways by small molecules simultaneously with antibodies modifying T-cell activation or exhaustion.This review covers some aspects of the current understanding of the immunological basis necessary to understand the rapidly developing therapeutic endeavours in cancer treatment, the clinical achievements made, and raises some burning questions for translational research in this field.

Rheumatic Syndromes Associated With Immune Checkpoint Inhibitors: A Single‐Center Cohort of Sixty‐One Patients

“…Vasculitis cases included necrotizing vasculitis, GPA flare, and giant cell arteritis flare (patients 1-4). There was 1 case of PMR flare and 3 cases of new-onset PMR-like syndrome (patients [5][6][7][8]. CTD included cases of diffuse systemic sclerosis-like syndrome and sicca syndrome (patients [9][10][11][12][13][14].…”

Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity

“…Having shown increased levels of immunosuppressive Tregs in mouse BCC-like skin, we next addressed the question of whether additional immunoregulatory mechanisms may support tumor immune escape. To this end, we performed a systematic screen for known immune checkpoints (Greil et al, 2017) via quantitative PCR of mouse BCC-like and control skin.…”

“…Given the clinical relevance of the PD-1/PD-L1 axis in cancer immunotherapy (Borghaei et al, 2015, Brahmer et al, 2015, Greil et al, 2017, Postow et al, 2015, we analyzed PD-1 expression on skin T cells of Ptch Dep and control mice. As shown in Figure 2b, 20% of all T cells expressed PD-1 in tumor lesions of Ptch Dep mice, whereas these cells were virtually absent in control skin (Fig.…”

The sound of tumor cell-microenvironment communication – composed by the Cancer Cluster Salzburg research network

“…How the immune system affects cancer development and progression has also been described by Greil and colleagues [10]. Cancer immunoediting involves alterations of the cellular composition and inflammatory cytokine profile in the tumor environment and provides an important link between cancer cells and the immune system.…”