# The role of TIM3 and CEACAM1 in anti-tumor function of human effector T cells

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $368,288

## Abstract

Solid tumors of the thorax continue to be a significant healthcare burden. Lung cancer remains the leading
cause of cancer death. Malignant pleural mesothelioma (MPM) is still without cure and portends a dismal
prognosis of about one year. One promising immunotherapeutic approach has been checkpoint blockade of
inhibitory receptors (IRs), like programmed death 1 (PD1). However, response to PD1 checkpoint blockade is
seen only in 20% of patients with solid tumors. Genetic modification of T cells (with chimeric antigen receptors
(CARs) and transgenic T cell receptors (TCRs)) does not prevent the hypofunction induced by PD1, supporting
the need to better understand the way IRs interact with the TME and the way they signal within T cells to
induce TIL hypofunction—in both naturally occurring tumor infiltrating lymphocytes (TILs) and adoptively
transferred, genetically engineered TILs. We previously showed that PD1 checkpoint blockade in xenograft
models of lung cancer and MPM is able to augment the control of flank tumor growth after one intravenous
dose of tumor-reactive human effector T cells. However, the augmentation is modest and tumors continue to
progress. Upon closer analysis of the TILs isolated from the flank tumors of the mice, we made a few
observations that helped us understand why the TILs were still suppressed in their anti-tumor function: 1) PD1
blockade was able to only partially preserve TIL function, 2) TILs had multiple IRs, other than PD1 upregulated,
3) some of these IRs seemed to increase in expression in response to PD1 blockade. One IR that was
upregulated in the TILs, particularly in the TILs from the mice that also received PD1 blockade, was TIM3.
When we subsequently treated flank tumor bearing mice that were given one adoptive transfer of T cells
intravenously with repeated intraperitoneal doses of anti-TIM3 antibody, a very minor effect was seen. This
may be due to a second receptor, CEACAM1, that has been shown to regulate the function of TIM3 on murine
T cells. Flow cytometric analysis of our own human T cells revealed the presence of four difference
populations: 1) TIM3-/CEACAM1-, 2) TIM3+/CEACAM1-, 3) TIM3-/CEACAM1+, and 4) TIM3+/CEACAM1+.
We presumed that the anti-TIM3 antibody interfered with not only the inhibitory TIM3 (i.e. that which was
coexpressed with CEACAM1 in population #4) but also interfered with the activating TIM3 (i.e. that which had
no CEACAM1 coexpression in population #2), hence resulting in a net minimal effect on T cell control of tumor
growth. CEACAM1 is also expressed on our tumor cells. In light of TIM3 being a promising target in cancer
immunotherapy, this proposal aims to clarify its function as well as its interplay with CEACAM1. We propose to
investigate the most important ligands for TIM3 (Aim 1), the impact of TIM3’s extracellular ligand-recognition
domain vs. TIM3’s intracellular signaling domains on TIM3-induced T cell hypofunction (Aim 2), the impact of
CEACAM1 on the anti-tumor acti...

## Key facts

- **NIH application ID:** 9978734
- **Project number:** 5R01CA219083-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Edmund K. Moon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,288
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978734

## Citation

> US National Institutes of Health, RePORTER application 9978734, The role of TIM3 and CEACAM1 in anti-tumor function of human effector T cells (5R01CA219083-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9978734. Licensed CC0.

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