RadVax: Cellular and molecular mechanisms of interaction between radiation and checkpoint blockade

To identify the molecular pathways involved in the synergy between radiation and checkpoint blockade including DNA damage response pathways, “danger/tissue damage” signals and innate immunity.

Identify potential targets to exploit through more rational use of radiation and also more targeted therapies.

Goals:

  • Identify key immune pathway changes induced independently by radiation and checkpoint blockade and define cellular and molecular pathways of crosstalk and synergy
  • Determine anatomically where immune augmentation is initiated during RadVax (i.e. role of lymphoid tissue versus tumor tissue)
  • Interrogate how radiation induced antiviral signaling in cancer and stromal cells is regulated by innate immune sensing pathways, exosomes containing non-coding RNA and how the induction of ISGs impacts immunotherapy.
  • Examine the contribution of stroma to production of immune activating signals after radiation therapy and test how these signals from stroma impact checkpoint blockade.
  • Examine known and novel DAMP pathways for roles in RadVax

Accomplishments:

  • Preliminary data demonstrate that exosomes from radiated cells preferentially induce interferon signaling in dendritic cells in vitro vs exosomes from unirradiated cells.  Next steps are to test in vivo (JS)
  • Developed a mouse model of lung adenocarcinoma to begin testing molecular mechanism of interact between radiation and ICB (SP)
  • Identified interferon signaling as major driver of resistance to immunotherapy in mouse tumor models (JB)
  • Downregulated T cell inhibitory ligand expression on resistant tumors in vivo using clinically available JAK inhibitor (JB)
  • Developed dosing schedule for JAK inhibitor delivery in combination with immunotherapy to enhance anti-tumor response in resistant tumors (JB)
  • Identified candidate interferon driven NK cell inhibitory ligands on tumors. Currently evaluating the effect of this signaling pathway on promoting resistance to anti-CTLA4 and anti-PD1 in mouse melanoma models (JB)
  • Developed mouse model of NSCLC and confirmed synergistic effect of anti-PD1 + JAK inhibitor (JB).
  • Designed x-50 flow panel for phenotyping mouse CD8/NK cells (JB).
  • Received IRB approval for Anti-PD1 + JAKi Trial (AM).
  • Discovered why tumor IFN signaling can have dichotomous effects on response to immune checkpoint blockade.
  • Identified how Tex cells can antagonize NK/ILC populations to interfere with response to immune checkpoint blockade, particularly in tumor with poor neoantigens.
  • Identified multivariable predictor of response/resistance to immune checkpoint blockade that is comprised of distinct sets of ISGs that represent the opposing functions of IFN signaling.
  • Phase II trial of anti-PD1 and JAK inhibitor for first-line metastatic non-small cell lung cancer has started.
  • Extended our understanding on how mutations in the IFN/JAK/STAT1 pathway can associate with response/resistance to immune checkpoint blockade.
  • Confirmed that interferon signaling in cancer versus immune cells predicts and promotes opposing effects on immunotherapy response across a broad range of cancer types.
  • Determined mechanistic differences in how type I versus type II interferon signaling in cancer cells impacts innate and adaptive immune cells to regulate response to immune checkpoint blockade.
  • Characterized key loci and transcription factors in epigenome of resistant tumors that contributes to immunotherapy resistance.

 

Publications:

  1. Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade Cell, 2016.
  2. Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Checkpoint Blockade Across Cancer Neoantigen Barriers (under review)
  3. Opposing Functions of Interferon Coordinate Adaptive and Innate Immue Responses to Cancer Immune Checkpoint Blockade. Cell, 178;4. 2019.
  4. Melidosian BX, Qiu, J, Benci JB, Xu Y, and Minn AJ: Cancer Epigenetic Control of Type I Interferon Signaling Regulates T Cell Fate Transition, (in preparation).

 

Project Participants: John Wherry, Andy Minn, Robert Vonderheide, Jacob Shabason, Joseph Benci, and Shetal Patel