Kure It-AACR Research Grants
The Kure It-AACR Research Grants represent a joint effort to promote and support innovative cancer research. AACR has awarded two grants through this partnership: the Kure It-AACR Grant for Kidney Cancer Research, intended for independent investigators to develop and study new ideas and approaches that have direct application and relevance to kidney cancer patients; and the Kure It-AACR Research Grant for Immunotherapy in Kidney Cancer, available to independent investigators to study immunological aspects of, or treatments for, kidney cancer. Applications are invited from researchers currently in their field as well as from investigators with experience in other areas of cancer research who have promising ideas or research approaches that can be applied to kidney cancer research. These grants support innovative research projects designed to improve the survival and quality of life of patients with kidney cancer and lead to individualized therapeutic options for treatment or the development of promising new cancer therapeutics for kidney cancer.
AACR-Kure It Research Grant for Immunotherapy in Kidney Cancer
W. Kimryn Rathmell, MD, PhD
Vanderbilt University Medical Center
Immunosuppression in the RCC tumor microenvironment
Scientific Statement of Research
The renal cell carcinomas (RCC) display a range of specific metabolic deficiencies that alter the tumor cell bioenergetics and alter their extracellular environment. In an era of rapidly expanding immunotherapy, a critical gap exists in our ability to augment the response to immune therapies. Our laboratory characterized defects in clear cell RCC (ccRCC) infiltrating lymphocytes, revealing functional metabolic deficiencies that can be overcome with exogenous manipulations of metabolic signals. The ability to manipulate the functionality of immune cells represents an opportunity to impact immune response with a finer level of control. We hypothesize that factors in the tumor microenvironment contribute to the blunted responsiveness immune cells, and that manipulations of immune cell metabolism can promote enhanced functionality. Modulating immune cell response via checkpoint inhibition is increasingly accessible, a strategy which we will apply in settings that mimic the microenvironmental conditions of both ccRCC and nonclear cell RCC.
Dr. Kim Rathmell is the Cornelius Craig professor of medicine and biochemistry and director for the Division of Hematology/Oncology at Vanderbilt, studying the molecular biology of renal cell carcinomas and rare tumors of the kidney. Her research examines the molecular underpinnings of tumors arising in the kidney, with funded studies examining chromatin biology, immune modulation, tumor metabolism, and angiogenesis. She additionally conducts clinical research and helped establish an alliance to increase research and awareness of rare renal tumors (RMC Alliance). She is broadly involved in the cancer genome atlas (TCGA) initiative, and co-led TCGA studies related to kidney cancers.
Acknowledgement of Support
The AACR-Kure It Research Grant for Immunotherapy in Kidney Cancer is a critical investment in basic science research. This award allows our laboratory to explore a new area of renal cell biology by focusing on the tumor microenvironment with potential to augment the rapidly emerging strategies of immune therapy.
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Kure It-AACR Research Grant for Immunotherapy in Kidney Cancer
Anna Meseguer, PhD
Head, Renal Physiopathology Group
Vall D'Hebron University Hospital Research Institute
constitute a new target for renal carcinoma immunotherapy?
Tumor cells and tumor-infiltrating lymphocytes adopt strategies to evade antitumor processes and may enhance the metastatic potential through the activation of chronic inflammatory signals. In the last years the blockade of immune checkpoints has emerged as one of the most encouraging approaches to trigger therapeutic antitumor immunity. Metastatic renal cell carcinoma RCC is one of the cancers where the new immunotherapy approach is generating more expectations and hope. For instance, treatment with agents able to block the interaction of the PDL1 with PD-1 produced durable responses in ~30% of patients with ccRCC. Unfortunately, an important limitation of those treatments is the fairly small proportion of patients who achieve clinical responses. In this context, the search for new immune checkpoints appears to be a necessity in order to increase the number of patients that could benefit of immunotherapy treatments.
We have recently elucidated some of the mechanisms that drive tumor growth and progression by TIM-1 receptor expression in ccRCC and observed a significant correlation between tumor malignancy and invasiveness with augmented TIM-1 ectodomain shedding, both in ccRCC patients and in ccRCC derived cell lines. We have also reported that ccRCC tumors overexpressing TIM-1 become engaged in the expression of a repertoire of molecules that favor tumor growth, apoptosis inhibition, angiogenesis, invasion and immune evasion. TIM-1 ectodomain shedding favors transcription of IL-6 and IL-11, and promotes further activation of the gp130/STAT3 pathway, by mechanisms that remain to be described both in tumor and in surrounding immune cells. TIM-1 is unique in being expressed in ccRCC cells and also in activated T lymphocytes, where seems to constitute a dual receptor, able to deliver both co-stimulatory and negative signals that leads to the activation or inhibition of T-cell effector function, respectively.
To date, nobody has addressed the issue on how ccRCC cells and the immune system interact through TIM-1, nor envisioned how identification of those mechanisms might provide with novel therapeutic targets. This project aims to study the mechanism through which TIM-1 shedding promotes transcription of relevant targets in tumor cells, and also to identify how the shed ectodomain promotes a cross-talk between the tumor and the host immune system, to further improve our knowledge on ccRCC tumor biology and provide with novel targets for effective and personalized treatment of ccRCC patients. As mentioned, metastatic renal cell carcinoma is one of the cancers where the new immunotherapy approach is generating more expectations but not all patients benefit from current therapies. It is of upmost importance to identify new avenues for the treatment of this devastating disease.
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