Tumor genotypes of EGFR-driven glioblastoma dictate diverse immune landscapes which confers selective responses to checkpoint blockade immunotherapy
Yeo, Alan.
2020
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Thesis (Ph.D.)--Tufts University, 2020.
Submitted to the Dept. of Cell, Molecular & Developmental Biology.
Advisor: Phil Hinds.
Committee: Al Charest, Gary Sahagian, and John Iacomini.
Keywords: Immunology, and Molecular biology.
The tumor microenvironment (TME) plays a significant role in how patients respond to therapy and during tumor progression. ... read moreRecent groundbreaking work suggests that tumor genotypes significantly influence distinct immune landscapes along with discrete mechanisms of immune suppression. Glioblastoma Multiforme (GBM) is an aggressive primary brain cancer with a poor median survival of approximately 15 months. Approximately 60% of GBMs harbor overexpression of EGFR of which 50% harbor a specific mutant of EGFR (EGFRVIII). Utilizing genetically engineered mouse models of EGFR-driven GBM, we determined how EGFRWT and EGFRvIII-driven GBM leads to distinct immune landscapes and how the differences in immune landscapes affect response to checkpoint blockade immunotherapy. We identified that strikingly, only combination checkpoint blockade of PD-1 and CTLA-4 was effective in prolonging survival in only EGFRWT driven but not in EGFRvIII-driven GBM. Mechanistic studies demonstrate that response to combination blockade is contingent on the balance of CD8 T-cell activation to immunosuppressive PMN-MDSC infiltrates. Interestingly, EGFRvIII GBMs have higher intratumoral PMN-MDSC infiltrates and more immunosuppressive cytokine milieu, rendering insensitivity to checkpoint blockade. Depletion of PMN-MDSCs can restore sensitivity to combination checkpoint blockade in EGFRvIII tumors and monotherapy checkpoint blockade in EGFRWT tumors. In addition, majority of immune related chemokines and cytokines are primarily expressed in CD45+ immune infiltrating cells suggesting an intricate tumor and immune cell interaction to mediate immune escape. Moreover, small molecule inhibition of EGFR can transform the EGFRvIII immune landscape by creating a pro-inflammatory cytokine milieu and augment efficacy of combination checkpoint blockade. Taken together, these results suggest that stratifying patients of particular tumor genotype may be beneficial for clinical trials of checkpoint blockade.read less - ID:
- vh53x922c
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