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Precise clustered regularly interspaced short palindromic repeats (CRISPR)-mediated genetic and epigenetic manipulation of the immune response has become a promising immunotherapeutic approach toward combating tumorigenesis and tumor progression. CRISPR-based immunologic reprograming in cancer therapy comprises the locus-specific enhancement of host immunity, the improvement of tumor immunogenicity, and the suppression of tumor immunoevasion. To date, the ex vivo re-engineering of immune cells directed to inhibit the expression of immune checkpoints or to express synthetic immune receptors (chimeric antigen receptor therapy) has shown success in some settings, such as in the treatment of melanoma, lymphoma, liver, and lung cancer. However, advancements in nuclease-deactivated CRISPR-associated nuclease-9 (dCas9)-mediated transcriptional activation or repression and Cas13-directed gene suppression present novel avenues for the development of tumor immunotherapies. In this review, the basis for development, mechanism of action, and outcomes from recently published Cas9-based clinical trial (genetic editing) and dCas9/Cas13-based pre-clinical (epigenetic editing) data are discussed. Lastly, we review cancer immunotherapy-specific considerations and barriers surrounding use of these approaches in the clinic., Graphical abstract, Alves et al. review the pre-clinical advancements in CRISPR-dCas9 and CRISPR-Cas13 epigenetic editing to improve anti-tumor immunity. These approaches are compared with current clinical applications of CRISPR-Cas9 genetic editing in cancer immunotherapy and paired with a discussion of how dCas9/Cas13 can work in combination with Cas9 to improve tumor elimination.

Summary: The heterogeneous pool of tissue-resident lymphocytes in solid organs mediates infection responses and supports tissue integrity and repair. Their vital functions in normal physiology suggest an important role in solid organ transplantation; however, their detailed examination in this context has not been performed. Here, we report the fate of multiple lymphocyte subsets, including T, B, and innate lymphoid cells, after murine liver and heart transplantation. In major histocompatibility complex (MHC)-matched transplantation, donor lymphocytes are retained in liver grafts and peripheral lymphoid organs of heart and liver transplant recipients. In MHC-mismatched transplantation, increased infiltration of the graft by recipient cells and depletion of donor lymphocytes occur, which can be prevented by removal of recipient T and B cells. Recipient lymphocytes fail to recreate the native organs’ phenotypically diverse tissue-resident lymphocyte composition, even in MHC-matched models. These post-transplant changes may leave grafts vulnerable to infection and impair long-term graft function.

Genetic diversity has underpinned the survival and expansion of human populations against a long history of varied microbial challenges, but may limit the universal immunogenicity of current vaccines against particular pathogens. Reduced or non-responsiveness is a barrier to total pathogen eradication for established vaccines, and remains the key impediment to licensure for a number of investigational vaccines. Genetic association studies have identified some determinants of vaccine immunogenicity, many of which act at single molecular interactions within complex pathways and networks. To date these immune modifying polymorphisms explain only a fraction of the known variation in vaccine responses and the most striking aspect of individualized immunity, immunodominance, remains a central issue in new vaccine design. Vaccine personalization is likely to require not only a systems biology approach to understand broad vaccine response phenotypes, but also an understanding that the specificity of antigen recognition unique to every vaccinee and restricted by their human leukocyte antigen (HLA) genotype, determines the unique CD4 and CD8 T cell and natural killer (NK) cell repertoires available for vaccine induction. This chapter discusses the role of HLA and non-HLA loci, and pathogen-specific adaptations relevant to vaccines and explores ways these could be exploited in vaccine design and personalization.

The human leukocyte antigen (HLA) genes in modern human populations reflect an intricate coevolution with pathogens that has occurred over millennia. These genes encode proteins involved in the presentation of self and nonself peptides to immune cells, and this sampling process allows for the detection of foreign infections, immunological memory, and immune surveillance but can also lead to adverse reactions resulting in autoimmunity and hypersensitivity. Not surprisingly, HLA genes are commonly associated with differential outcomes to infections and inflammatory diseases. At the genomic level, the HLA genes reside within the major histocompatibility complex (MHC) on the short arm of chromosome six. This region is characterized by high levels of polymorphism due to positive selection and segmental duplications giving rise to closely related proteins with overlapping function and extensive linkage disequilibrium spanning several megabases of sequence resulting in the inheritance, en bloc, of combinations of specific alleles or haplotypes. Although some of these features can be observed elsewhere in the human genome, the MHC lies on one extreme of the spectrum. Regions containing homologous genes of the HLA system in nonhuman primates exhibit a similar pattern with additional lineage-specific modifications. This chapter will cover the evolution of the human MHC, focusing on the HLA class I genes.

Adverse drug reactions (ADRs) represent a tremendous source of morbidity, mortality and cost in modern medicine. The human leukocyte antigen (HLA) genes are highly polymorphic and encode proteins that are integral to T-cell-mediated immunity to infectious pathogens. A growing body of data demonstrates that T-cell immune responses are also etiologic for many ADRs and that certain HLA genotypes predispose to the development of drug hypersensitivity. Well-characterized examples of HLA-associated drug hypersensitivity reactions include those involving abacavir, carbamazepine, allopurinol, nevirapine, flucloxacillin, and amoxicillin-clavulanate. The mechanisms underlying HLA-associated ADRs are the subject of exciting research and recent findings have identified key interactions between small molecule pharmaceuticals and HLA proteins thereby elucidating the immunopathogenesis of certain ADRs. Drug hypersensitivity preventive strategies developed as part of this work, such as stratified approaches to avoid abacavir in all those carrying HLA-B*57:01, have been translated from discovery into routine clinical use. In the future it is predicted that our enhanced understanding of HLA-drug interactions will lead to the successful implementation of high-throughput preclinical and early premarketing drug toxicity screening approaches that will lead to safer and more effective drug design and development.