Tumor-induced escape mechanisms and their association with resistance to checkpoint inhibitor therapy

Abstract

Immunotherapy aims to activate the immune system to fight cancer in a very specific and targeted manner. Despite the success of different immunotherapeutic strategies, in particular antibodies directed against checkpoints as well as adoptive T-cell therapy, the response of patients is limited in different types of cancers. This attributes to escape of the tumor from immune surveillance and development of acquired resistances during therapy. In this review, the different evasion and resistance mechanisms that limit the efficacy of immunotherapies targeting tumor-associated antigens presented by major histocompatibility complex molecules on the surface of the malignant cells are summarized. Overcoming these escape mechanisms is a great challenge, but might lead to a better clinical outcome of patients and is therefore currently a major focus of research.

Keywords: Immune escape; Immunotherapy; MHC; Resistance; TIMO XIV; Tumor.

Fig. 1

Tumor escape mechanisms. Different immune escape strategies of tumors discussed in the review are depicted. The figure shows mechanisms based on a epigenetic modifications (e.g., histone acetylation, DNA methylation); b regulation at the transcriptional level (e.g., for MHC class I, selected transcription factors and promoter motifs are shown); c post-transcriptional regulation by miRNAs or RBPs; d reduced classical MHC class I surface expression; e impaired IFN-γ signaling pathway; f expression of immune inhibitory molecules and/or g establishment of an immunosuppressive TME. h Novel factors identified in the regulation of MHC class I surface expression

Fig. 2

Resistance mechanisms to cancer immunotherapy. The schematic diagram summarizes the main mechanisms involved in adaptive and acquired resistance to different immunotherapies including iCPI