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DHHC3-mediated Regulation of Anti-Tumor Immunity

A novel, alternative approach to PD-L1 blockade for enhancing anti-tumor immunity by recruiting both an adaptive and innate immune response.

  • Therapeutics

Project Overview

  • There is a pressing need to develop additional and combinatorial cancer treatments with programmed death-ligand 1 (PD-L1) blockade to improve tumor clearance in resistant or untreatable tumors.
  • Dana-Farber scientists have developed a new technology targeting the DHHC3 protein that results in reduced tumor growth in animal models.
  • This alternative approach to PD-L1 blockade is available for licensing.

Technology

In the last decade, it has become clear that mobilization of the immune system greatly aids in the treatment of many cancer types, including breast cancer. Unfortunately, tumor cells make immune checkpoint blockade molecules such as programmed death-ligand 1 (PD-L1) to avoid detection by immune cells.

Programmed death-ligand 1 (PD-L1) is expressed at the surface of many cancer cells and triggers the inactivation of anti-tumor T-cells, thus allowing tumors to escape immune surveillance. Direct inhibition of the immune checkpoint inhibition, PD-L1, has limitations in the treatment of breast cancer among many other cancers. Therefore, there is a pressing need to develop additional and combinatorial cancer treatments with PD-L1 blockade to improve tumor clearance in resistant or untreatable tumors.

Scientists at Dana-Farber have discovered a new link between the protein acyltransferase DHHC3 and PD-L1 expression. DHHC3 knockdown in tumor cell lines results in marked decrease in surface expression of PD-L1. It is also observed that palmitoylation of CMTM6 is largely dependent on the presence of DHHC3. These results strongly suggest that ablation of DHHC3 causes a deficiency in CMTM6 palmitoylation, rendering it unable to support expression of PD- L1. Furthermore, in vivo data demonstrate that DHHC3 ablation from breast and prostate tumor cells results in markedly diminished tumor growth in xenograft mouse models. 

Benefits:

  • Ability to recruit both adaptive and innate immune anti-tumor responses via DHHC3 inhibition 
  • Low toxicity associated with DHHC inhibition 
  • Targetable by small molecule inhibitors 

Team Members: Martin E. Hemler, PhD, Chandan Sharma, PhD

Applications

A novel, alternative approach to PD-L1 blockade for enhancing anti-tumor immunity in resistant or untreatable tumors.

Opportunities

Dana-Farber is looking for the right partner with an interest in licensing these assets for further development. 

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Team Members