Future Challenges in Cancer Resistance to Immunotherapy

Abstract

Cancer immunotherapies, including checkpoint inhibitors, adoptive T cell transfer and therapeutic cancer vaccines, have shown promising response rates in clinical trials. Unfortunately, there is an increasing number of patients in which initially regressing tumors start to regrow due to an immunotherapy-driven acquired resistance. Studies on the underlying mechanisms reveal that these can be similar to well-known tumor intrinsic and extrinsic primary resistance factors that precluded the majority of patients from responding to immunotherapy in the first place. Here, we discuss primary and secondary immune resistance and point at strategies to identify potential new mechanisms of immune evasion. Ultimately, this may lead to improved immunotherapy strategies with improved clinical outcomes.

Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

“…Tumour metabolism also limits the effectiveness of immunotherapies by affecting the tumour mutation rate and antigenicity [ 145 ]. Metabolism is tightly linked to DNA repair through chromatin remodelling, epigenetic modifications, and regulation of the redox status [ 146 ].…”

“…Finally, CAFs in the TME may also contribute to immunotherapy resistance by several mechanisms. Firstly, the release of immunosuppressive cytokines TGF-β and IL-6 by CAFs lead to reduced proliferation and trafficking capacity of antigen-presenting DCs, thereby impairing T cell priming against tumour antigens [ 145 , 148 ]. CAFs also directly upregulate immune checkpoint ligands on their surface, including PD-L1 and PD-L2 [ 149 , 150 ].…”

Advances in Anti-Cancer Immunotherapy: Car-T Cell, Checkpoint Inhibitors, Dendritic Cell Vaccines, and Oncolytic Viruses, and Emerging Cellular and Molecular Targets

“…While CAR T cell therapy has been greatly successful in the treatment of B-cell malignancies, barriers arise when translating this therapy to solid tumours, reviewed elsewhere [30]. There are three main factors hindering the use of CAR T cells for the treatment of solid cancers; firstly, the desmoplastic nature of the solid TME creates a physical barrier for T cells to enter [31].…”

Nucleic Acid-Based Approaches for Tumor Therapy

“…Up to now, several antibodies addressing CTLA-4, PD-1, and its ligand PD-L1 have been implemented in cancer therapy regimens [ 25 , 26 ]. However, response rates are quite low, and relapse often occurs due to resistance development [ 434 , 435 , 436 , 437 , 438 ]. Moreover, immune checkpoint blockade is effective only if the number of tumor-reactive Teff is high enough at the beginning of treatment [ 434 , 439 , 440 , 441 , 442 ].…”