This new R01 application is submitted in response to Funding Opportunity RFA-CA-15-008 “Research
Answers to NCI's Provocative Questions”. The hypothesis to be tested is in response to PQ3. We hypothesize
that the benefit afforded by immune surveillance to the individual and populations of cancer patients may
depend on the levels of aneuploidy and expression of the Major Histocompatibility Complex (MHC) complex
Class II (MHCII) in the tumor. We further predict that a population of individuals defined by tumors with high
aneuploidy and low MHCII expression is at higher risk of progression and poor outcome, and
unresponsiveness to immunotherapy by regulating the size and composition of intra-tumor immune infiltrates.
Within this new paradigm, we also propose to investigate the possible causative mechanism of aneuploidy-
induced proteotoxic stress. The study will be a combination of genomic analyses and immunological
interrogation in UCSD Moores Cancer Center patients, and will ultimately seek validation in through TCGA
data as well as data from immunotherapy trials. We propose four Aims.
(1) To validate aneuploidy/MHC II as predictors of progression and clinical outcome. TCGA data will be
interrogated to relate an association between aneuploidy and levels of MHCII expression to overall survival.
and response in immunotherapy (ICPi) trials. (2) To measure markers of natural immune response in
cancer patients grouped according to aneuploidy/MHC II status. We will study the size and clonality of
tumor-infiltrating T cells by profiling TCR reactive with TERT, an antigen expressed by cancer cells at every
stage of differentiation, as a proxy of the autochthonous anti-cancer response. By comparing tumor-infiltrating
T cells to circulating T cells, we expect to determine if (a) tumor the aneuploidy/MHCII signature predicts T cell
infiltration, and (b) lower immune T cell infiltration displays high TCR heterogeneity. (3) To determine whether
aneuploidy/MHCII status interferes with response to ICPi therapy. We will determine if high aneuploidy/low
MHCII expression impairs immune reactivation after ICPi therapy, and use immunoscore from responder and
nonresponder patients. (4) To determine whether proteotoxic stress is the mechanism by which
aneuploidy interferes with immune response. Because aneuploidy induces proteotoxic stress, the ensuing
UPR provides a mechanistic link between cancer cell biology and immune surveillance. In vitro and in vivo
experiments using cells with pharmacologically-induced aneuploidy will be used to determine the extent to
which UPR cell nonautonomous effects may account for a disruption of local immunity, i.e., number and
characteristics of tumor infiltrating myeloid cells.
We believe that an analysis at the interface between cancer genomic and immune surveillance may
reveal general rules for immune-mediated control of cancer. This may help stratify patients and their clinical
trajectory, and predict clinical responses to immunotherapy more accurately.