Tumor Microenvironment

The tumor immune environment can be thought of as ecosystem-like network of interacting cells, signaling molecules, extracellular matrix, and mechanical cues that can support tumor growth, protect the tumor from host immunity, foster therapeutic resistance, and support metastases.  Our group is focused on immune modulation strategies to create “danger” or “rejection” signals that make the tumor appear more dangerous to the immune system and transform the tumor-immune environment from tumor protecting to tumor killing.

Cancer cells that grow to form invasive tumors may have escaped the immune system by creating a tumor-immune environment that allows the lesion to escape from immune attack.  Modification of the tumor environment can involve the down regulation of major histocompatibility complex molecules (MHC) or the induction of immune inhibitory cytokines and chemokines, leading directly to T cell anergy and the expansion and activation of immune suppressive cell populations such as regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSC).  Studies from our group, and from others, suggest that the tumor-immune environment can be actively manipulated to revert to a pro-inflammatory Type I environment which will allow the activation of antigen presenting cells (APC) and the induction of cytokines such as IFN-g, TNF-a, and IL-12 that are associated with cancer eradication.  The CVI is actively evaluating multiple immumodulatory approaches that could be used alone or in combination with vaccination and T-cell therapy to remodel the tumor immune environment and stimulate an effective anti-tumor immune response.  These strategies include the activation of antigen presenting cells via stimulation of toll like receptors (TLRs) and elimination of immune suppressive cell populations (Tregs and MDSC) , leading to  enhanced local cytokine production and a Th1-polarized microenvironment that favors tumor cell killing by cytotoxic T lymphocytes.

Active Modulation of the Tumor Microenvironment

  • Depleting T regulatory cells.  We have shown that depletion of Tregs using ONTAK, a fusion protein of IL-2 and diphtheria toxin, can significantly inhibit tumor growth in a mouse model of breast cancer (Knutson et al, JI, 2006).  This finding has been translated into a clinical trial in breast and ovarian cancer patients.
  • Topical Imiquimod for breast cancer chest wall metastasis.  Recurrent chest wall disease occurs in up to 35% of breast cancer patients and may be the sole site of disease.  There are very few treatment options for chest wall metastasis.  Using a mouse model of breast cancer, we have shown that topical treatment with imiquimod cream can inhibit tumor growth (Lu et al, JI, 2010).  This finding has been translated into a clinical trial by our group.
  • TLR8 agonist to enhance NK cell function and ADCC.  We have characterized VTX-2337as a novel TLR8 agonist.  It selectively activates myeloid DC and induces high levels of TNF-a and IL-12.  VTX-2337 also enhances NK cell function and augments antibody-dependent cell-mediated cytotoxicity (ADCC) (Lu et al, CCR 2011).  This finding has led to a clinical trial in head and neck cancer patients testing the combination of VTX-2337 with cetuximab mAb therapy.
  • Natural products to enhance anti-tumor immunity.  We have found that protein-bound polysaccharide (PSK), a hot water extract from Trametes Versicolor, has potent TLR2 agonist activity.  PSK inhibits tumor growth in a CD8 T cell and NK cell-dependent manner (Lu, et al, CCR 2011).  PSK also enhanced human NK cell function and augments HER2-targeted monoclonal antibody therapy (Lu et al, CCR, 2011).  This finding is being translated into an upcoming clinical trial in breast cancer patients testing the combination of PSK , trastuzumab, and HER2-targeted CD4 peptide vaccine.

Future Directions

We are exploring the development of combinatorial therapies using multi-modality immune-modulation for cancer treatment.  We continue to identify new agents that will enhance antigen presenting cell activation facilitating cross priming at the tumor site and generating of polyclonal tumor specific immunity.  We are evaluating other agents that can create the “rejection” signal in tumors and are identifying surrogates of rejection that might be detected in serum or peripheral blood as a means of either identifying early response or continuing treatment until the “rejection” signal is reached.  We are hopeful that altering the chronic inflammatory environment of the tumor to one that will support tissue destruction and control self regulation will be key in optimizing T cell directed immune based therapies.