Project Summary-Abstract
Renal cell carcinomas (RCC) are among the 10 most common cancer types in man (6th) and woman (8th)
worldwide. Most RCC are clear cell carcinomas (>80%) that represent an atypical cancer type in many ways
including the intrinsic resistance to many chemotherapeutics, sensitivity to anti-neoangiogenesis, and sensitivity
to immune checkpoint inhibitors but with very low mutational burden. The treatment landscape of RCC has been
changing rapidly in the last couple of years but still with very low complete response rate even with the most
updated treatment regimens. Those “atypical” features of RCC prompted us to perform a comprehensive single
cell RNA sequencing for human ccRCCs and paired bloods. We found that tumor induced Tregs are highly
suppressive to effector T cells and could be the major immune cells conferring the immune suppressive tumor
microenvironment (TME). These TI-Tregs have the typical signs of cellular senescence, including the expression
of p16, p21, BCL-XL, senescence-associated secretory phenotype (SASP), and the activation of ß-galactosidase
(ß-Gal). The group recently reported the development of the first-in-class BCL-XL degraders, i.e. the Proteolysis
Targeting Chimeras (PROTACs, referred to as BCL-XL-Ps). DT2216, a lead BCL-XL-P, targets BCL-XL to the
von Hippel-Lindau (VHL) E3 ligase; and PZ15227 targets BCL-XL to the cereblon (CRBN) E3 ligase for
ubiquitination and subsequent degradation by the proteasome. We have found these two senolytics are very
effective in eliminating TI-Tregs and activate anti-tumor immunity in our recent publication. Based on these novel
findings, we hypothesize that aging- and cancer-associated cellular senescence – including senescence from
immune cells – is critical in RCC pathogenesis and cancer progression via modulating the tumor immune
microenvironment. Understanding these fundamental questions is important for rational design of therapeutic
regimens towards to RCC that remains an urgent and unmet clinical need. Specific Aim 1 is to establish the
mechanistic connection between cellular senescence – in particular Treg senescence – and RCC with special
focus on the modulation of tumor immune microenvironment. Aim 2 is to determine the therapeutic efficacy of
senolytic depletion of TI-Tregs and common therapeutics in RCC. The team has expertise in clinical renal cancer,
cellular senescence, in particular the senolytic drug development and senescence tracing, cancer models and
cancer immunology. We will establish the role of tumor infiltrating Tregs in immune modulation within the tumor
microenvironment and determine the efficacy of targeting senescent Tregs in RCC cancer therapy, by combining
with anti-neoangiogenesis drugs or immune checkpoint inhibitors.