Blogs

Histologic and immune characterization of cutaneous immune-related adverse events induced by immune checkpoint inhibitors

Summary:

Investigators from MD Anderson examined the immune checkpoint blockade-associated immune-related adverse events (IRAE) of the skin in treated patients. Surprisingly, in 15 patients with lichenoid, morbilliform and other rashes that they profiled with a 770-gene immune panel, they demonstrated that THY1/CD90 is the most consistently up-regulated transcript. CD90 is maintained throughout vertebrate evolution (as well as being found in some invertebrates) and was the first T cell marker identified. It is encoded on chromosome 11q22.3, close to CD3 and NCAM/CD56, and expressed on many cell types including thymocytes, neurons, mesenchymal stem cells, hematopoietic stem cells, NK cells, high endothelial venules, renal glomerular mesangial cells, fibroblasts, and follicular dendritic cells (FDC). Its molecular weight is 25–37 kDa. Thus, it is the smallest of the immunoglobulin gene superfamily members, heavily N-glycosylated and glycophosphatidylinositol (GPI) anchored. They also demonstrated enrichment for so-called M2 macrophages. Although M2 macrophages have been shown to express CD90, the nature of their studies precluded demonstrating that they were the major driver for high expression of the transcript. For this DC-oriented Digest, no increase in either resting or activated DC were found, nor was there evidence of increased TH2 cells. Implications here allow consideration of targeting either CD90 or M2 macrophages specifically to limit the cutaneous IRAEs.

Overcoming immunotherapy resistance in bladder cancer with a novel antibody-drug conjugate RC48

Biomineralized engineered Lactococcus lactis-based in situ vaccination enhances antitumor immunity via sequential activation of chemo-immunotherapy

We launched a local immunotherapy and oncolytic virus section in  JITC   five years ago. Here, authors report on a program building on previous success of using  in situ  delivery of a genetically modified bacteria,  Lactococcus lactis  to deliver FLT3 ligand and OX40 ligand at the site of tumor to expand and activate DCs. Now, they have incorporated these bacteria into a magnesium-based metal-organic framework (MOF) to further delivery of immunogenic chemotherapeutic agents, specifically cisplatin and vincristine with pH-sensitive drug release. After demonstrating the remarkable utility of combining these approaches in murine models, calling this approach D&V@FOLactis, they demonstrated a clear abscopal effect in untreated tumors. Evaluation of D&V@FOLactis-treated tumors demonstrated remarkable increases in DC expression of the costimulatory molecules, CD80 and CD86. They then moved to treat three patients with various histologic cancers with a combination of local radiation therapy and direct injection. Modest antitumor effects were noted in combined sites compared with irradiated sites that were not injected. Serum cytokines including IL-6, CXCL10, and CCL3 were found as well but not at levels that would be considered a cytokine storm.

HPV16 E6 and E7 expressing cancer cells suppress the antitumor immune response by upregulating KLF2-mediated IL-23 expression in macrophages

Summary: 

One of the great successes in modern cancer prevention has been the ability to immunize during adolescence, individuals to human papilloma virus serotypes associated with promoting both cervical cancer as well as head and neck cancer. The transformative ability of the oncogenic serotypes of the virus is the ability to sequester p53 and retinoblastoma protein by the transforming capabilities of the viral genes E6 and E7. Interestingly, when expressing these viral genes in B16 melanoma, the Kast group at the University of Southern California found that this enhanced the expression of IL-23 in sorted macrophages (CD11b⁺, F4/80⁺) but not DCs (F4/80⁻, CD11c⁺). Enhanced, nominally immunosuppressive IL-23 was apparently induced by the Kruppel-like factor, KLF2. Both KLF2 and KLF7 have been observed in tumor-associated macrophages. KLF2 was also directly shown to serve as a transcriptional up-regulator of IL-23 by expressing the gene in RAW macrophages. IL-23⁺ macrophages were observed within patient HPV+ tumors but not within CD11c⁺ DCs. Three conserved zinc fingers of 21 or 23 amino acids are found in KLF2. Its deletion is embryonic lethal. It has a major role in T cells such that specific ablation limits emigration from the thymus but its role in macrophages has been far less studied. Recent studies from investigators at UC Berkeley have demonstrated expression in tissue resident macrophages, including embryonically derived large cavity macrophages (LCMs) within serous cavities as well as alveolar macrophages. Further evaluation and extension of the findings of Kast regarding KLF2⁺ macrophages in the setting of cancer are expected. Furthermore, how E6 and E7 drive tumors to recruit or sustain such macrophages is of great interest.