The Bone Metastasis Immunological Niche: Unraveling Its Complexity and Role in Therapy Response and Resistance
Abstract
Renal cell carcinoma (RCC) is the seventh most common cancer, with ~330,000 cases diagnosed and more than ~140,000 deaths per year worldwide. Bone metastasis represents a lethal complication in 35%-40% of patients. RCC is richly infiltrated by immune cells and particularly responsive to immunotherapy, a type of treatment that activates the immune system against the cancer cells to kill them. However, despite an unprecedented success, only a subset of patients benefits from this treatment due to variable activation of the immune system or emerging resistance (which occurs when cancer cells adapt and escape from death, re-initiating tumor growth), and toxicity is often very high. Another common feature of RCC is the particular abundance of tumor blood vessels, which support tumor growth by providing nutrients and removing waste products. Medical therapies that target blood vessels, such as different types of tyrosine kinase inhibitors (TKIs), are particularly effective for treating RCC and are clinically applied alone or in combination with immunotherapy. Interestingly, this combination resulted in improved survival and lower rates of severe toxicity compared to immunotherapy alone, becoming a frontline treatment. Unfortunately, RCC bone metastases are more challenging to treat than primary tumors and most other metastatic sites, and the reasons for such treatment failure are unclear. As a matter of fact, due to the severity of bone metastasis (which often prevents patients afflicted with this complication to be enrolled in clinical trials) and the difficulty in collecting and processing bone samples, limited knowledge is available on the role of the immune cells in bone metastasis progression and response to treatment. This is of great interest because the bone is a known site of therapy resistance and lethality for patients; therefore, a better understanding of the cellular and molecular players involved in this process would help to identify why therapeutic agents fail and how we can improve treatment strategies. With this work, we aim to fill an important knowledge gap and shed light on the black box of bone metastasis, both before and after application of TKIs and immunotherapy, alone or in combination. This is made possible through the effort of a uniquely qualified team, which includes medical oncologists, basic/translational scientists, immunologists, bone experts, orthopedic oncologists, neurosurgeons, and interventional radiologists. Our teamwork will allow accessing bone metastasis samples acquired from patients during surgery, followed by analysis of tumor, immune and bone cells, and the clinical translation of these findings in a rational application of therapeutic agents. Specifically, our analyses will comprehensively define the cellular composition and molecular characteristics of tumor, bone, and immune cells and will investigate the cellular spatial distribution by using advanced three-dimensional microscopy. Information on the spatial context is of great importance, because the localization of immune cells within tumors can significantly impact their activity, and the proximity of tumor cells to bone cells can increase their survival and therapy resistance. As a short-term result, our studies will lay the foundations for a future clinical trial, to be opened and pursued within the 3-year term of the grant, with the aim to more precisely characterize the evolution of bone metastases after exposure to TKI treatment in combination with immunotherapy. This study will confirm the mechanisms of response and resistance that occur in bone in order to define a more accurate clinical administration of therapies that target and modulate the bone microenvironment, to improve survival and quality of life for patients afflicted with this lethal disease. Our approach will improve patient treatment by delineating innovative strategies to break tumor cell resistance to currently applied therapies for p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210466
Entities
People
- Eleonora Dondossola
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army