Schema of the components of the tumor microenvironment
T cells are expected to defend us from cancer cells. Unfortunately, the immune system fails to contain tumor growth and metastasis. The tumor microenvironment contributes to the failure of the immune system to fight cancer cells. A current major interest in this laboratory is to study how ion channels contribute to the ineffective surveillance of T lymphocytes in solid tumors. Particularly, we focus on the response and adaptation of ion channels of T lymphocytes to the tumor microenvironment, especially to low oxygen levels (hypoxia) and increased concentrations of adenosine.
Kv1.3 channel function is reduced in tumor infiltrating lymphocytes in head and neck cancers (Chimote et al., Cancer Research 2017)
Hypoxia and adenosine are characteristic of the solid tumor microenvironment and they have been associated with a poor outcome. Both hypoxia and adenosine have been shown to inhibit the function of tumor infiltrating lymphocytes. Our group demonstrated that hypoxia inhibits the potassium channel Kv1.3 and effectively blocks T cell activation i.e., T cells are no longer able to combat the disease at hand. We described the mechanisms by which hypoxia reduce Kv1.3 channel expression and function. We also discovered that adenosine suppresses T cell motility and cytokine release via inhibition of KCa3.1 channels. These studies have introduced ion channels as mediators of the immune suppressive tumor microenvironment. Indeed, we discovered that the functional capability of tumor infiltrating T lymphocytes (TIL) in head and neck cancer (HNC) patients is reduced and this impaired function correlates with reduced Kv1.3 channels.
Reduced KCa3.1 channel activity and chemotaxis in head and neck cancer T cells (Chimote et al, Science Signaling 2018)
We also discovered that the activity of KCa3.1 channels in circulating cytotoxic T cells of HNC patients is impaired and activation of these channels restores the chemotactic abilities of TIL. Overall, our studies position ion channels among the elements involved in reduced immune surveillance in cancer and open the possibility of targeting ion channels as new therapeutic interventions in solid malignancies.
Resistance to immunotherapy
Immunotherapies are revolutionizing the way cancer is treated. However, despite the impressive responses to immunotherapy, there is still a relatively large subset of patients who do not respond or eventually relapse. The mechanisms that determine which patients do or do not respond to immunotherapy treatment remain poorly understood. Our laboratory is interested in studying the role that ion channels play in mediating the response to immunotherapies, particularly immune checkpoint inhibitors. These are highly translational studies performed utilizing clinical samples from HNC patients receiving pembrolizumab (anti-PD1 blocking antibody). The clinical specimen are studied in our laboratory to dissect possible mechanisms of resistance to immunotherapy. Complementary in vitro and in vivo studies in humanized mouse models of cancer are also performed. These studies will potentially identify biomarkers to stratify patients that would benefit from an anti-PD1 therapy, and support the development of new combination therapy strategies.
Newton, H.S., Gawali, V.S. , Chimote, A.A. , Lehn, M.A., Palackdharry, S.M., Hinrichs, B.H., Jandarov, R., Hildeman, D., Janssen, E.M., Wise-Draper, T.M., & Conforti, L. PD1 blockade enhances K+ channel activity, Ca2+ signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer Journal for Immunotherapy of Cancer 2020; 8:e000844. doi: 10.1136/jitc-2020-000844
Chimote, A.A., Gawali, V.S., Newton, H.S., Wise-Draper, T.M., & Conforti, L. A compartmentalized reduction in membrane-proximal calmodulin reduces the immune surveillance capabilities of CD8+ T cells in head and neck cancer Frontiers in Pharmacology Feb 28;11:143. doi: 10.3389/fphar.2020.00143. eCollection 2020.
Chimote A.A., Balajthy A., Arnold M. J., Newton H., Hajdu P., Qualtieri J., Wise-Draper T. and Conforti L. A defect in KCa3.1 channel activity limits the ability of CD8+ T cells from cancer patients to infiltrate an adenosine-rich microenvironment. Sci Signal. 2018 Apr 24;11(527). pii: eaaq1616. doi: 10.1126/scisignal.aaq1616. PMID: 29692361
Conforti L. Potassium channels of T lymphocytes take center stage in the fight against cancer. Commentary. Journal for ImmunoTherapy of Cancer 2017, 5: 2; DOI 10.1186/s40425-016-0202-5.
Chimote A.A., Hajdu P., Sfyris A.M., Gleich B., Wise-Draper T., Casper K. and Conforti L. Kv1.3 channels mark functional competent CD8+ tumor infiltrating lymphocytes in head and neck cancer. Cancer Res January 1 2017, 77 (1): 53-61; DOI:10.1158/0008-5472.CAN-16-2372.
Conforti L, Petrovic M, Mohammad D, Lee S, Ma Q, Barone S, Filipovich AH.: Hypoxia regulates expression and activity of Kv1.3 channels in T lymphocytes: a possible role in T cell proliferation. J Immunol. 2003 Jan 15;170(2):695-702.PMID: 12517930.