# The Impact of Cancer on the Pathophysiology of Sepsis

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $296,400

## Abstract

Summary
Patients with malignancy are nearly ten times more likely to develop sepsis than the general population, and
cancer represents the most common co-morbidity in septic patients. Moreover, cancer is also the co-morbidity
associated with the highest risk of death in sepsis, and hospital mortality can exceed 50% in patients with
cancer and either sepsis or septic shock. However, the etiology behind the increased mortality seen in
cancer patients who develop sepsis compared to healthy patients who develop sepsis is not well
understood. This proposal aims to understand the cellular and molecular mechanisms by which the presence
of cancer increases mortality during sepsis. We have identified and characterized distinct coinhibitory
receptor profiles on CD4+ T cell populations in the setting of cancer and sepsis. Importantly, these
differences are functionally relevant because some coinhibitory receptor blockade strategies have
fundamentally different efficacy in the setting of cancer and sepsis compared to sepsis alone. First, we found
that PD-1 blockade fails to improve survival during sepsis in animals with pre-existing malignancy even though
this strategy is effective in sepsis alone. The mechanisms underlying this will be investigated in this proposal.
Next, we found that TIGIT blockade is effective in preventing mortality from sepsis in animals with pre-existing
malignancy, but interestingly is ineffective in sepsis in previously healthy animals. These results illuminate the
fact that immunologic changes occurring as a result of pre-existing malignancy can impact the responsiveness
to immunotherapy for sepsis, and highlight the need to design specific immunomodulatory therapies to
reverse immune dysregulation in patients with cancer and sepsis. Finally, we have identified a pathway
that may be responsible for the global changes in coinhibitory receptor expression and responsiveness in
cancer septic hosts. IL-27 has been shown to potently regulate the expression of multiple coinhibitory
receptors on the surface of T cells in models of both cancer and autoimmunity. Our preliminary data
demonstrate a profound synergistic increase in serum concentrations of IL-27 in cancer septic hosts
as compared to either sepsis alone or cancer alone, demonstrating that high serum IL-27 is associated with
increased coinhibitory signaling in the setting of cancer and sepsis. Thus, the overarching hypothesis of this
proposal is that increased levels of IL-27 present in cancer septic hosts results in the increased expression of T
cell coinhibitory molecules on distinct subsets of CD4+ T cells, both regulatory and effector, that results in
functional dysregulation of immune responses and increased mortality in cancer septic hosts. Interrogation of
this hypothesis will elucidate novel immunotherapeutic pathways to control T cell coinhibitory receptor
expression and improve mortality and immune dysregulation in cancer septic hosts.

## Key facts

- **NIH application ID:** 10189636
- **Project number:** 5R01GM104323-08
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Craig M Coopersmith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $296,400
- **Award type:** 5
- **Project period:** 2013-06-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189636

## Citation

> US National Institutes of Health, RePORTER application 10189636, The Impact of Cancer on the Pathophysiology of Sepsis (5R01GM104323-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10189636. Licensed CC0.

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