Metastatic melanomas are aggressive tumors that respond poorly to chemotherapy and radiation and promptly acquire resistance to targeted therapy. While immune checkpoint inhibitors (ICIs) can induce sustained melanoma remission, nearly half of patients are intrinsically resistant to ICIs, in part because their tumors are too large to be cleared by the immune system or are immunologically ?cold? and lack immune recognition necessary to generate anti-tumor T effector cells. Our preliminary data show that senescence- inducing therapy enhances melanoma-cell intrinsic pro-inflammatory program driven by transcription factor NF- ?B. We identified the RIG-I-Like Receptor (RLR) pathway as a candidate NF-?B inducer. This pro-inflammatory program involves enhanced antigen presentation and secretion of chemokines that recruit antigen-presenting cells into the tumor. We also found that senescent cells overexpress checkpoint molecules PD-L1 and Galectin 9, which can inhibit T cells by binding their inhibitory receptors PD-1 and TIM-3, respectively. This suggests that senescence-inducing therapy can enhance recognition of tumor antigens while targeting senescence- specific immune checkpoints can promote adoptive T cell responses against these antigens. Despite its immunogenic properties, therapeutic application of senescence-inducing agents is complicated by the reports that persistent senescent cells may promote tumor metastasis, relapse, and chemo-resistance. Here we hypothesize that we can safely improve melanoma immunogenicity by inducing tumor cell senescence for a limited time, followed by elimination of persistent senescent cells using senolytic drugs that specifically kill senescent cells. This novel therapeutic approach is expected to be effective by: 1) directly blocking tumor cell growth and survival, 2) activating RLR-mediated tumor cell intrinsic immuno-stimulatory signals, and 3) making tumor cells vulnerable to inhibitors of PD-L1/PD1 and Galectin 9/TIM3 immune checkpoints.
Three specific aims will examine these mechanisms. In the first aim we will establish the optimal dosing schedule for combined senescence-inducing and senolytic therapy and determine the direct anti-tumor efficacy in an immune-deficient mouse model. A pre-clinical trial using our extensively characterized melanoma PDXs will be conducted to estimate response rate to senescence-inducing and senolytic drug combinations and to identify response-predictive biomarkers.
Second aim will investigate the mechanisms whereby senescence-inducing and senolytic therapy facilitates the innate immune sensing of tumor focusing on the role of RLRs. We will examine whether deficiency in RLR signaling can abrogate NF-?B activation, chemokine secretion, and immune cell recruitment into senescent tumors.
Aim three will determine if senescence-inducing and senolytic therapy augments immune checkpoint inhibitor (ICI) responses. We will utilize anti-PD-L1 and anti-TIM3 agents to target senescence-cell specific immune checkpoints. These studies will provide a preclinical basis for clinical development of rational combinations of senescence-inducing and senolytic agents.

Public Health Relevance

The focus of this project is on pre-clinical development of a novel therapeutic concept where melanoma tumor growth is controlled by directly targeting tumor cells and by making them easier targets for the anti-tumor immune response. This research will improve our understanding of tumor-host interactions, and enable effective therapeutic modulation of these interactions. This work should to have a profound impact on the survival of metastatic melanoma patients by advancing a novel therapy for patients who fail to respond to standard of care treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
1R37CA233770-01
Application #
9639889
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Venkatachalam, Sundaresan
Project Start
2018-12-01
Project End
2023-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
965717143
City
Nashville
State
TN
Country
United States
Zip Code
37240