Premium
Pembrolizumab treatment increases chemotaxis of cytotoxic T cells in head and neck cancer patients within the adenosine‐rich tumor microenvironment
Author(s) -
Newton Hannah S.,
Chimote Ameet A.,
Gawali Vaibhavkumar S.,
Palackdharry Sarah,
Hildeman David,
Janssen Edith,
Wise-Draper Trisha,
Conforti Laura
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02047
Subject(s) - pembrolizumab , tumor microenvironment , immunotherapy , medicine , head and neck squamous cell carcinoma , cytotoxic t cell , immune system , cancer research , t cell , cancer immunotherapy , chemotaxis , immunology , cancer , oncology , head and neck cancer , biology , receptor , biochemistry , in vitro
Head and neck cancer (HNC) is the sixth most common cancer worldwide with a five‐year survival rate of 50%. Immunotherapy has been emerging as a promising treatment modality as conventional treatment strategies (surgery, chemotherapy and radiation) have limited efficacy and cause debilitating co‐morbidities. Immunotherapy harnesses the patient’s own immune system to fight disease. Targeting the immune system is crucial because immune cell (specifically cytotoxic T cell) infiltration into the tumor microenvironment (TME) and subsequent cytotoxicity is critical for tumor elimination. Pembrolizumab, an anti‐PD‐1 (programmed cell death‐1 receptor) antibody, is an immunotherapy currently approved for metastatic or recurrent unresectable HNC and is in clinical trials for curative intent. While there have been promising long‐lasting clinical responses to Pembrolizumab, many patients still do not respond. Thus, it is critical to understand the mechanism of action of Pembrolizumab in order to reduce treatment resistance. Moreover, it has been shown that Pembrolizumab increases cytotoxic T cell density in the TME; nevertheless, the underlying mechanism is not fully understood. However, it is known that there is an increased accumulation of adenosine (Ado), an anti‐inflammatory purine nucleoside, in the TME of HNC patients, which inhibits T cell chemotaxis by blocking the function of the potassium ion channel, KCa3.1. Therefore, to elucidate possible effects of Pembrolizumab on T cell chemotaxis, we studied KCa3.1 activity and subsequent chemotaxis in CD8 + peripheral blood T cells (PBTs) of naïve (never treated) HNC patients before/after Pembrolizumab treatment (n=25) via electrophysiological and 3D chemotaxis experiments. Furthermore, Pembrolizumab treated patients were categorized as responders (R) or non‐responders (NR) based on treatment response (i.e., reduction in tumor viability with a cutoff of ≥20% for R). We observed that Pembrolizumab increased the KCa3.1 activity in post‐treatment patient PBTs by 29.8% (p=0.026). Because we observed an increase in KCa3.1 activity in treated patients, we next assessed whether there was an effect on the chemotaxis of PBTs in presence of Ado. While Ado inhibited the chemotactic ability in treatment naïve PBTs by 53.9% (p<0.001, n=22), we determined that post‐treatment R PBTs were not inhibited by Ado (p = 0.142, n=11) whereas post‐treatment NR PBTs were inhibited by Ado (p = 0.005, n=10). These data support a role of ion channels and chemotaxis in patient response to Pembrolizumab and could lead to better understanding of the effect of Pembrolizumab in immune cell infiltration into the tumor and, ultimately, its mechanism of action/resistance. Support or Funding Information DoD CA160714; T32CA117846; 2R01 CA95286