Changes in tumor-specific antigenicity overtime in melanoma patients undergoing adoptive T cell therapy

Most tumors, and most likely "all" tumors, express one or more non-synonymous somatic mutations that generate sufficient number of novel HLA/peptides that potentially could be targeted by T cells. However, similar to infections, when under immune pressure tumor can also develop escape variants by modulating its HLA/peptide landscape. 

This is what new study published in journal Nature found in tumor patients. For this study, the authors (who are associated with AIMM Therapeutics) sequenced patients tumor mRNA at different time points (before or after adoptive cell therapy) and found that some of the tumor-specific HLA/peptides had disappeared [overtime] and some new tumor-specific HLA/peptides became enriched instead. 

Of note, within each patient almost all of T cell reactivity to tumors were patient-specific (i.e. private HLA/peptide) and did not share sequence similarities with publicly known shared tumor-associated epitopes. For example, analysis of patient's CD8+ T cell specificity against a panel of >200 MHC-multimers containing known shared tumor-associated epitopes demonstrated that only 1.24% of the CD8+ T cells responded to three different "shared" gp100 epitopes. The rest were patient's specific. 

For this study two melanoma patients had their tumors mRNA sequenced and underwent autologous adoptive tumor-specific T cell therapy. In one patient, initial tumor mRNA sequencing revealed  501 non-synonymous mutated genes. Most of CD8+ T cell reactivity were directed to two HLA/peptides complexes: KIAA0020 p.P451L (KIA P>L) and ribosomal protein RPL28 p.S76F (RPL28 S>F).

Around 1 year later, however, patient's CD8+ T cell reactivity was only observed against the KIAP>L neo-antigen, and not against RPL28S>F and tumor mRNA sequencing confirmed absence of mutant allele encoding the RPL28S>F neo-antigen within tumors harvested at a later time.

Similarly, in an another patient undergoing similar procedures, the authors found that initially melanoma patient's CD8+ T cells were specific for the neo-antigens echinoderm microtubule associated protein like 1 p.R64W (EML1R>W), Septin-2 p.R300C (SEPT2R>C), and CAD protein p.R1854Q (CADR>Q).  

However, later analysis revealed no significant T cell reactivity against EML1R>W, CADR>Q neo-antigen and SEPT2R>C neo-antigens. Instead, it showed T cell response towards the Programmed Cell Death Protein 10 p.P28S (PDCD10P>S) neo-antigen. Indeed, tumor mRNA sequencing confirmed that while mutant allele encoding the SEPT2R>C neo-antigen that was present in the original tumor, it was selectively lost in the tumor samples harvested later, and that RNA for novel PDCD10 neo-antigen had increased > 40-fold in later time points instead.

These data points to two important considerations: first, tumor undergoes changes in their mutational landscape and can evade T cell detection and second, most tumor mutations are patient's specific. This means that adoptive immunotherapy using single T cell specificity would be less efficient overtime and that tumor vaccines using "generic-shared" tumor epitopes would provide no benefits in most patients. 

David Usharauli

      

The adaptation of microglia (brain macrophages) to brain development

Microglia is a brain-specific macrophage lineage that seeds the developing brain tissue in utero (embryonic) and contributes to "patterning and wiring of the brain in early development and contribute to homeostasis throughout life". Since brain is cocooned from the rest of the body by blood-brain barrier (BBB), it is not clear whether microglia, as a member of innate immune system, is responsive to signals generated within immune system.

New study in Science suggests that brain resident microglia undergo time-dependent step-wise upgrades and retains sensitivities to signals derived from immune system and microbiota.

Basically for this study the authors analyzed gene expression profile of microglia (both from single cell and from the pool) harvested from brain at different developmental stage (in utero (embryonic), newborn and adult).      

Interestingly and relevant for medicine, the authors could show that systemic activation of immune system by poly I:C could disrupt normal formation of newborn microglia by switching its developmental program to more adult microglia-like setting. 

Such changes in newborn microglia can potentially underlie neuro-developmental challenges in babies born to mothers experiencing immune activation (viral infections) during pregnancy.   

David Usharauli

Absence of NOD2 signaling protects against chemical[STZ]-induced diabetes

Experimental models developed in "clean" laboratory mice rarely translates to human diseases. For example, NOD mice spontaneously develop Type 1 diabetes, as susceptible humans do, however pancreatic tissue pathology does not match. 

There is another model of T1D in mice called treptozotocin (STZ)-induced diabetes. STZ is toxic to insulin producing β cells in pancreas and drive T1D in a T cell-dependent manner. In new study published in Journal of Experimental Medicine the authors showed that treptozotocin induced T1D depended on gut flora derived muramyl dipeptide → NOD2 signaling.

The authors found that NOD2^-/- mice, but not NOD1^-/- or Rip2^-/- mice, were resistant to STZ effect.

Interestingly, similar protective effect against T1D were seen in WT mice treated with broad-spectrum antibiotics and STZ. However, addition of NOD2 ligand muramyl dipeptide reversed protection in [antibiotic + STZ] treated mice.

This study showed that NOD2 ligand, muramyl dipeptide derived from gut microbiota, contributes to T1D in STZ-treated mice.

David Usharauli