Cancer is incredibly difficult to treat because it’s not just cancer cells we’re up against. It’s the cancer cells, plus all the other non-cancer cells, including some immune cells, that the tumor has corrupted and tricked into sculpting the surroundings to suit the tumor’s survival.
This area that encompasses and surrounds tumors--including all the cells, structures, and molecules in it--has come to be known as the tumor microenvironment (TME). The TME controls cancer development and progression, and can even determine how patients respond to treatment. As the third session here at #CICON16 can attest, we now recognize that if we’re going to beat cancer, we’re going to have to tackle the TME along with it.
Wolf H. Fridman, M.D., Ph.D., co-director of the Cordeliers Research Center (INSERM) in Paris, France, began the session by stressing the importance of the immune composition in the TME, which can help us predict the course of the disease, especially in colorectal cancer (CRC). For instance, TMEs with a density of dendritic cells (DCs) and T cells are associated with better outcomes, compared to immunosuppressive tumors with myeloid-derived suppressor cells and regulatory T cells. This information can also guide treatment decisions. Fridman, as part of a group assembled by Fight Colorectal Cancer and the Cancer Research Institute (CRI), helped define some of these guidelines for improving our efforts against CRC.
Next, Shannon Turley, Ph.D., a former CRI-funded postdoctoral fellow now principal scientist of the cancer immunology team at Genentech, highlighted how fibroblastic reticular cells (FRCs) promote proper immune activity through their ability to recruit DCs and enable them to activate T cells. Turley discovered that these FRCs regulate the mechanical flexibility of lymphoid organs such as lymph nodes, which is necessary for effective immune responses. Unsurprisingly, tumors often exploit these mechanisms to protect themselves from attack.
This physical component of immune activity was echoed by David G. Denardo, Ph.D., an assistant professor at the Washington University School of Medicine, who spoke later in the session. Denardo deals with pancreatic cancer, which is notorious for dense and fibrous tumors that prevent infiltration of anti-cancer immune cells. This makes checkpoint inhibitors ineffective since the T cells they act upon can’t even get into the tumor. To address this, Denardo is targeting FAK (focal adhesion kinase), which controls this pro-cancer architecture and is often hyperactivated in pancreatic cancer cells. In mice, FAK inhibition sensitized tumors to checkpoint inhibition. Furthermore, adding the chemotherapy gemcitabine to the regimen improved responses even more and significantly improved survival. This approach is now being tested in a phase Ib trial, and, so far, there have been no adverse effects in patients.
On a different note, Taha Merghoub, Ph.D., the co-director of the Ludwig Collaborative Laboratory at Memorial Sloan Kettering Cancer Center, showed how the TME can also protect tumors through metabolic mechanisms. Cancer cells often produce lactate, a base component of lactic acid, at a high rate, which accumulates in the TME and inhibits T cell proliferation. However, when the cancer cells’ lactate transporters were blocked, it prevented them from discarding lactate into the TME and restored T cell proliferation. This highlights the potential of metabolic approaches to enhance T cell activity and enhance immunotherapy responses.
We also heard from Shimon Sakaguchi, Ph.D., of Osaka University, who discovered regulatory T cells (Tregs), which can protect cancer by suppressing anti-tumor T cells. For this achievement, he received the 2004 William B. Coley Award from CRI. At CICON16, Sakaguchi highlighted his recent identification of distinct Treg-like subsets that can behave in drastically different ways: some appear pro-cancer, others anti-cancer. Further characterizing these cells and teasing apart their different behaviors will help us anti-cancer immunotherapy strategies.
The bacteria that reside within our body, known as the microbiota, was next on the program. They were the sole focus of the fourth session here at CICON16, so check back soon to hear what the experts had to say!