# Metabolic Contributions of Individual Cellular Compartments to the Diversity of the Tumor Microenvironment in Renal Cell Carcinoma

> **NIH NIH F30** · VANDERBILT UNIVERSITY · 2021 · $30,776

## Abstract

PROJECT SUMMARY
Deregulating cellular energetics and avoiding immune destruction are considered hallmarks of cancer.
Stimulating anti-tumor immunity is now a chief goal of cancer therapy. The success of immune checkpoint
blockade (ICB) therapy demonstrates the tremendous promise of this paradigm, but still only a minority of
patients have durable responses with this modality of therapy. I propose that altered metabolic programs in the
tumor microenvironment (TME) may be linked to dysfunctional anti-tumor immune responses. By revealing these
interactions, there may be new opportunities to improve the efficacy of immunotherapy. I have generated novel
data demonstrating that myeloid cells across tumor models uptake significantly more glucose in the TME, while
transformed cells appear to be glutamine consuming. Renal Cell Carcinomas (RCC) are metabolically altered
tumors that are characterized by a complex and abundant immune cell infiltrate. It is well established by our
group and others that these tumor-infiltrating T cells are metabolically compromised and have limited antitumor
capacity. Even though ICB has improved RCC patient survival, only a minority of patients have complete
responses with these T cell stimulating agents. The unique genetics of RCC may contribute to this
aforementioned suppressive TME. In clear cell RCCs, the loss of the tumor suppressor von Hippel Lindau (VHL)
is a necessary event for tumorigenesis. Additionally, in a subset of aggressive Type II papillary RCCs, the loss
of fumarate hydratase (FH) or other defects in the tricarboxylic acid cycle are required for tumor formation. These
genetic events were defined by my mentor WK Rathmell and others. These genetic events across RCC results
in accumulation of the oncogenic transcription factors (TFs) hypoxia inducible factor 1 and 2. With
accumulation of these TFs, RCC tumor cells shift their energetic requirements by decreasing their reliance on
the tricarboxylic acid cycle and mitochondrial respiration while increasing cellular glycolysis. Therefore, RCC is
uniquely posed to further study the impact of tumor cell metabolism on lymphoid and myeloid cell fate and
function. This project will apply novel immunocompetent, non-immunogenic CRISPR/Cas9 models to study the
effect of RCC genetic events (VHL and FH loss) on immune infiltration and activation. In these models, I
will also examine the differential outcomes of inhibiting glucose and glutamine uptake on immune cell
fitness and function in the TME. This work will be complemented by studies that employ in vitro primary
human RCC organoid models to examine the impact of genetic and chemical perturbations on human
tumor resident immune cell metabolism. This study will ultimately shed light on the heterotypic nature of tumor
metabolism. By understanding the divergent metabolic capacities of the key cell types in the heterogenous TME,
this work will increase our capability to support anti-tumor capacity of infiltrating immune c...

## Key facts

- **NIH application ID:** 10155823
- **Project number:** 1F30CA247202-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Bradley Reinfeld
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $30,776
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155823

## Citation

> US National Institutes of Health, RePORTER application 10155823, Metabolic Contributions of Individual Cellular Compartments to the Diversity of the Tumor Microenvironment in Renal Cell Carcinoma (1F30CA247202-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10155823. Licensed CC0.

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