Over the last half century, it has become well established that cancers can elicit a host immune response that can target them with high specificity. Only within the last decade, with the advances in high-throughput gene sequencing and bioinformatics approaches, are we now on the forefront of harnessing the host's immune system to treat cancer. Recently, some strides have been taken toward understanding effective tumor-specific MHC I restricted epitopes or neoepitopes. However, many fundamental questions still remain to be addressed before this therapy can live up to its full clinical potential. In this review, we discuss the major hurdles that lie ahead and the work being done to address them.

Zinc (Zn) is an essential metal for development and maintenance of both the innate and adaptive compartments of the immune system. Zn homeostasis impacts maturation of dendritic cells (DCs) that are important in shaping T cell responses. The mechanisms by which Zn regulates the tolerogenic phenotype of DCs remain largely unknown. In this study, we investigated the effect of Zn on DC phenotype and the generation of Foxp3+ regulatory T cells (Tregs) using a model of Histoplasma capsulatum fungal infection. Exposure of bone marrow–derived DCs to Zn in vitro induced a tolerogenic phenotype by diminishing surface MHC class II (MHCII) and promoting the tolerogenic markers, programmed death–ligand (PD-L)1, PD-L2, and the tryptophan degrading enzyme, IDO. Zn triggered tryptophan degradation by IDO and kynurenine production by DCs and strongly suppressed the proinflammatory response to stimulation by TLR ligands. In vivo, Zn supplementation and subsequent H. capsulatum infection supressed MHCII on DCs, enhanced PD-L1 and PD-L2 expression on MHCIIlo DCs, and skewed the Treg–Th17 balance in favor of Foxp3+ Tregs while decreasing Th17 cells. Thus, Zn shapes the tolerogenic potential of DCs in vitro and in vivo and promotes Tregs during fungal infection.

No abstract

No abstract

The majority of JAK2 V617F -negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin ( CALR ), resulting in a common carboxyl-terminal mutant fragment (CALR MUT ), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALR MUT -specific T cells are rare in patients with CALR MUT MPN for unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies in patients with CALR MUT MPN from two independent cohorts. We observed that MHC-I alleles that present CALR MUT neoepitopes with high affinity are underrepresented in patients with CALR MUT MPN. We speculated that this was due to an increased chance of immune-mediated tumor rejection by individuals expressing one of these MHC-I alleles such that the disease never clinically manifested. As a consequence of this MHC-I allele restriction, we reasoned that patients with CALR MUT MPN would not efficiently respond to a CALR MUT fragment cancer vaccine but would when immunized with a modified CALR MUT heteroclitic peptide vaccine approach. We found that heteroclitic CALR MUT peptides specifically designed for the MHC-I alleles of patients with CALR MUT MPN efficiently elicited a CALR MUT cross-reactive CD8 + T cell response in human peripheral blood samples but not to the matched weakly immunogenic CALR MUT native peptides. We corroborated this effect in vivo in mice and observed that C57BL/6J mice can mount a CD8 + T cell response to the CALR MUT fragment upon immunization with a CALR MUT heteroclitic, but not native, peptide. Together, our data emphasize the therapeutic potential of heteroclitic peptide–based cancer vaccines in patients with CALR MUT MPN.