Immunogenomics: using genomics to personalize cancer immunotherapy

Abstract

While the use of genomic data has the potential to revolutionize patient care, there is still much work to be done with regard to the transformation of host-tumor interactions into favorable clinical outcomes for our patients. High-throughput technologies, such as next-generation sequencing (NGS), have rapidly advanced our understanding of oncology, and we are learning that most tumors do not simply possess consistently mutated genes that are responsible for tumorigenesis, facilitating the need for personalized cancer therapy. A T cell-dependent mechanism of cancer progression was discovered in 2012, providing a potential link to cancer immunotherapy. Since then, an antibody against cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), ipilimumab, and three programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors, pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq), were approved by the Food and Drug Administration (FDA) in the USA. In this review article, based on evidence that has been emerging in the literature over the last decade, we will discuss the basis for including genomic data in immunotherapy regimens, the current progress in identifying biomarkers targetable by immune checkpoint blockade, and the application of these therapies in modern oncology programs. Going forward, the clinical application of NGS in personalized oncology programs could include dose monitoring and adjustment or the development of individualized vaccines or other personalized therapies based on the mutational landscape. The continued identification of new neoantigens and the efficient mobilization of tumor-reactive lymphocytes in patients with cancer will promote the advancement of immunotherapy using personalized NGS-guided technologies.

Metal Drugs and the Anticancer Immune Response

“…For sure, an enhanced number of mutations and translocations would help the immune system to recognize a malignant cell clone as "non-self". 267 This fits well to the observation that cancer immunotherapy with checkpoint inhibitors is successfully used in tumors harboring a very high tumor mutation burden (TMB) including melanoma, NSCLC, and urothelial carcinomas. 124,163 However, it needs to be considered that classical driver mutations of cancer with an immunogenic potential are extremely rare, as impressively summarized for highly mutated malignant melanoma by Schumacher and Schreiber.…”

“…This is based on the intricate crosstalk of cancer cell signaling and metabolic circuits with the tumor immune-environment. Consequently, the predictive power of defined genetic signatures (despite not representing neo-antigens) for cancer immunotherapy response is intensely investigated in the field of immunogenomics. , …”

Recent Advances of Gold Compounds in Anticancer Immunity

“…This is closely related to anticancer metal chemotherapy drugs which are believed to have mutagenesis in many cases. Indeed, the increased number of mutations as well as translocations would support adaptive immune system to identify “non-self” malignant neoantigens (Siniard and Harada, 2017 ). Although the interaction between gold-based drugs and DNA is weaker than that of platinum, they also induce some mutations.…”

Whole Exome and Transcriptome Analyses Integrated with Microenvironmental Immune Signatures of Lung Squamous Cell Carcinoma

“…Immune defenses, on the other hand, are governed by tumor stroma, including basement membrane, extracellular matrix, vasculature, and cells of the immune system (7)(8)(9). Most cells in tumor stroma have some capacity to suppress a tumor, although this capacity changes as the cancer progresses; invasion and metastasis can follow (10)(11)(12)(13).…”