Oncotarget

Research Papers:

Lactate induces PD-L1 in HRASG12V-positive oropharyngeal squamous cell carcinoma

Alexander K. Verma, Shanta M. Messerli and W. Keith Miskimins _

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Oncotarget. 2020; 11:1493-1504. https://doi.org/10.18632/oncotarget.27348

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Abstract

Alexander K. Verma1, Shanta M. Messerli1 and W. Keith Miskimins1

1 Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD, USA

Correspondence to:

W. Keith Miskimins,email: Keith.Miskimins@sanfordhealth.org

Keywords: oropharyngeal cancer; lactate; Ras; anti-tumor immunity; PD-L1

Received: January 10, 2019     Accepted: November 13, 2019     Published: April 28, 2020

ABSTRACT

Intratumoral lactate production negatively correlates with survival and tumor clearance in the setting of human papillomavirus positive oropharyngeal squamous cell carcinoma (HPV-positive OPSCC). Robust anti-tumor immune activity is required for tumor clearance in human patients and animal models of this disease, and intratumoral lactate interferes with this process. While lactate is known to directly inhibit T cell activity, recent evidence has demonstrated that lactate can affect gene expression in multiple cell types. We therefore sought to determine if lactate in the tumor microenvironment could aid immune evasion by inducing the expression of immune checkpoint co-inhibitors. Using a mouse cell line transformed with HPV16 E6, E7, and HRASG12V, we determined that OPSCC cells carrying the HRASG12V mutant showed significantly increased expression of PD-L1 in the presence of extracellular lactate. Furthermore, we demonstrate here that lactate activates the MEK/ERK pathway in Ras-mutated cells.


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