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### T Cells in Autoimmunity and Tumor Immunity

by Kai Wucherpfennig, M.D., Ph.D.

Chair, Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute
Professor of Neurology, Harvard Medical School

- unique features of MS-associated HLA
  - HLA region is a major susceptibility locus for MS (known for a long time)
  - how do MHC II genes confer susceptibility?
  - genetic map - HLA-DR/HLA-DQ interval
    - HLA-DR15 haplotype specifically affected
- first they determined the crystalline structure of HLA-DR15

  - MHC Class II protein presents as self-peptide to T cells
  - there is a critical area in the binding site of HLA-DR proteins that are important for multiple autoimmune diseases - P4 pocket binding site
  - different features in different autoimmune diseases
  - beta70 and beta71 residues have different charges
  - diverse feature of MHC II system - determines peptide diversity
  - ex. in Type 1 diabetes - critical polymorphism at beta57 (P9 pocket) that determines binding strength to HLA-DQ sites

- self-reactive T cells are limited during thymus development
  - later, some can escape negative regulation and cause death
  - these cause autoimmune disease such as MS
  - studying properties of these strange TCR's
- usually peptide antigen is between the helices of the MHC receptor (on the T cell)
  - almost all microbe-specific T cells look the same
  - self-reactive T cells have a different protein domain structure
- in a self-reactive TCR
  - fewer contacts with the antigen, but stronger bonds (compared to anti-microbial TCR binding)
  - only specific amino acids in the antigen determine whether the TCR can interact with the antigen
- created fake lipid bilayer with MHC II and adhesion protein
  - interactions with TCR's captured using images
  - first exposure - form microclusters then start to move around
  - self-reactive TCR's moved a lot more than the anti-microbial one
  - virus-specific TCR's emit more cytokine signalling
- self-reactive TCR's have lower affinity than virus-specific
  - however, it's not because the TCR's dissociate sooner from the antigen (both types stay bound to the antigen for the same amount of time following interaction)
  - actually because the self-reactive TCR's don't bind to antigens as quickly

### Clinically Relevant Genomic Alterations in Neurosurgical Oncology

by Ganesh Shankar, MD PhD

Instructor of Neurosurgery, Massachusetts General Hospital

- what determines precision in neurosurgical oncology
  - surgery (resection or open biopsy)
    - diagnosis
    - cytoreduction
    - look at
      - history
      - physical exam
      - anatomy
  - adjuvant
    - chemotherapy
    - XRT
    - targeted therapy
    - look at
      - tumor histology
      - molecular markers
      - genomic alterations
      - (he wants to use these in the surgery part of the treatment)
  - outcome
    - increased PFS/OS
    - decrease treatment related morbidity
  - role of genomics in oncology
    - tumor genetics
      - exome
      - genome
      - transcriptome
  - patient w/ craniopharyngioma (benign, locally dangerous)
    - vision/headache problem
    - two histology versions
      - ** (something I missed) \_**
      - papillary - BRAF V600E mutation highly recurrent, patient had this mutation
    - treatment
      - put on BRAF antagonists
      - 82% reduction tumor
    - this alteration was actually a hotspot that could be detected in the blood
      - could mean in the future that you don't need a surgical operation to determine this type of targeted treatment
  - looking at NGS for examples
    - rhabdoid meningioma - very aggressive, tend to recur, short survival rate but also treatment co-morbidities
      - classified as grade 3
      - certain hallmark somatic/germline events that segregate various menangiomas
      - **Shankar and Santagata Neuro-Oncology 2017 paper on chart with figure on certain mutations for each type of tumor** - look at this paper
      - histological features - can't really tell if the meningioma has rhabdoid features
      - try to use NGS for this - found they only has mutations correlated with grade 1 meningiomas, put aside data set
      - BAP1 tumor suppressor
        - involved in cell cycle progression, self-renewal, and differentiation
        - somatic mutations in BAP1 have been reported in various cancers
      - then did analysis using microarrays on BAP1 expression (on the original data set talked about above) across 322 meningiomas (which were originally determined by IHC)
        - the patients who had loss of BAP1 had the aggressive progressors
        - some of these patients had a germline CNV w only 1 copy of BAP1 and then lost the other one through a somatic mutation
    - spinal cord astrocytomas
      - difficult to treat surgically
      - rare, usually pediatric
      - about a quarter are high grade
      - post-op survival ~1 year, usually have decreased neurological function
        - have to have big surgeries for essentially just a needle biopsy and then some sort of duraplasty (? - look this up)
      - wanted to look for molecular biomarkers for these patients so they can just do a lumbar puncture
        - known that:
          - grade 2/3 gliomas tend to have highly repetitive alterations in the growth factor pathways (e.g. BRAF) (pediatric), IDH1/2 (adults)
          - grade 4, (pediatric) histone, (adult) RAS/p53
        - NGS on cohort - found H3F3A mutation for pediatric
          - a lot of papers came out demonstrating midline gliomas demonstrated highly recurrent mutations in these H3F3 pathways
    - diffuse astrocytomas
      - intraop diagnosis of glioma can be challenging
      - 10-15% of intraop can't tell what you're dealing with, have to do watchful waiting
      - a lot of patients have to have a second resection after the initial biopsy operation
    - glioma subtypes are characterized by recurrent molecular genetic alterations
      - turns out if you look at just IDH1 and TERT promoter status, you can predict which patients survived better
      - made a rapid, quantitative assay they could use intraop
      - PACMAN probe (?)
      - qPCR method - 35 minutes
      - this allowed a second opinion combined with the histology for diagnosis
    - how to turn a research assay into a clinically-usable assay
      - used for CNS tumors
      - any kind of tumors that may have an interest in TERT, BRAF mutations
      - don't have to wait weeks for NGS
    - want to be able to do surgical resection then inject slow-release agents at the surgical margin while the patient waits for chemo/radiation
    - IDH mutations sensitive to certain inhibitors
      - NAMPT inhibitors - toxic to the body in levels required to reach the brain
      - want to develop ways to lay down particles that elute NAMPT inhibitors over a period of time (microparticle delivery system)
      - release drugs up to 7-8 days
      - demonstrated NAMPT that they can target IDH mutant cells
      - need to know the molecular phenotype of the tumor before using this treatment
      - tested in IDH1 orthotoic glioma model - reduction in tumor growth when the microparticles were used against IDH1 human astrocytomas
        - increase in survival based on this study