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 activity of human effector T cells (Aim 3).

Public Health Relevance

Inhibitory receptors (IRs) represent a significant hurdle for tumor-infiltrating lymphocytes within the microenvironment of solid tumors, and although significant progress has been made in early phase clinical trials treating different solid malignancies by blocking programmed death 1 (PD1), the majority of patients do not response. Another IR, T cell immunoglobulin and mucin-domain containing-3 (TIM3), is a promising target that has the potential to increase the response rate, but much is still unclear about how TIM3 impacts effector T cell function, particularly the possibility of its function being regulated by another IR, carcinoembryonic antigen-related cell adhesion molecule1 (CEACAM1). The goal of this proposal is to better understand how TIM3 functions and interacts with CEACAM1 to effect effector T cell anti-tumor function.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Mccarthy, Susan A
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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