The Efficacy of Tumor Mutation Burden as a Biomarker of Response to Immune Checkpoint Inhibitors

Abstract

Cancer is one of the leading causes of death in the world; therefore, extensive research has been dedicated to exploring potential therapeutics, including immune checkpoint inhibitors (ICIs). Initially, programmed-death ligand-1 was the biomarker utilized to predict the efficacy of ICIs. However, its heterogeneous expression in the tumor microenvironment, which is critical to cancer progression, promoted the exploration of the tumor mutation burden (TMB). Research in various cancers, such as melanoma and lung cancer, has shown an association between high TMB and response to ICIs, increasing its predictive value. However, the TMB has failed to predict ICI response in numerous other cancers. Therefore, future research is needed to analyze the variations between cancer types and establish TMB cutoffs in order to create a more standardized methodology for using the TMB clinically. In this review, we aim to explore current research on the efficacy of the TMB as a biomarker, discuss current approaches to overcoming immunoresistance to ICIs, and highlight new trends in the field such as liquid biopsies, next generation sequencing, chimeric antigen receptor T-cell therapy, and personalized tumor vaccines.

Keywords: immune checkpoint inhibitors; immunotherapy; tumor microenvironment; tumor mutation burden.

Figure 1

Tumor microenvironment. (A) The TME develops around tumor cells and is composed of the extracellular matrix, immune cells, mesenchymal stromal cells, blood vessels, and cancer-associated fibroblasts. (B) The tumor is able to grow and metastasize due to fibroblast activation, cytokine signaling, angiogenesis, and immune evasion. (C) Important immune cells in the TME include T cells, B cells, natural killer cells, and macrophages. (D) Research has shown that the gut microbiome has an integral role in the anti-tumor immune response and subsequently impacts a patient’s response to ICIs (Created with BioRender.com; (accessed on 15 January 2023)).

Figure 2

Neoantigens and current immune checkpoint inhibitors. (A) Tumor mutation burden (TMB) is the total number of somatic mutations found in the cancer cells’ DNA. (B) On the surface of tumor cells, neoantigens are presented and subsequently recognized by T cells. (C) Treg cells can reduce the cytotoxic T cell response against transformed cells. (D) Types of cancer treatment include surgery, chemotherapy, radiation, and immunotherapy. ICIs are a type of immunotherapy that promotes T cell activation. CTLA-4 and PD-1 signaling can be blocked by current ICIs. (E) PD-1 is an inhibitory checkpoint with an immunosuppressive role. Anti-PD-1 antibodies allow for T cell activation (Created with BioRender.com; (accessed on 15 January 2023)).

Figure 3

New trends in the field. (A) CAR T cell therapies involve the adoptive transfer of T lymphocytes reprogrammed to attack tumor cells by targeting antigens such as CD-19. Challenges have arisen for CAR T cell therapies in solid tumors due to the difficulty penetrating the dense stroma of the tumors and the immunosuppressive TME that decreases chemokine expression. A potential solution is the utilization of specific TAAs. (B) Personalized tumor vaccines utilize tumor neoantigens to generate an anti-tumor response and apoptosis of tumor cells. (C) Liquid biopsies and molecular characterization of ctDNA allow for targeted NGS with gene panels such as MSK-IMPACT^® (Created with BioRender.com; (accessed on 15 January 2023)).

Figure 4

Immunoresistance to ICIs. (A) Patients can have primary resistance to ICIs and not respond to treatment at all or can have acquired resistance and undergo a period of initial response to ICIs followed by progression of malignancy and stable resistance. (B) Cold tumors have an immunosuppressive TME and show a poor response to immunotherapy, while hot tumors have an immunosupportive TME and are responsive to immunotherapy (Created with BioRender.com; (accessed on 15 January 2023)).