Abstract
IntroductionOX-40 co-stimulatory signaling plays a role in mounting anti-tumor immune responses and clinical trials targeting this pathway are ongoing. However, the association of with OX-40 protein expression with clinical outcomes and pathological features in non-small cell lung cancer (NSCLC) are largely unknown.MethodsSurgically-resected stage I-III NSCLC specimens (N = 100) were stained by immunohistochemistry (IHC) for the following immune markers: OX-40, PD-L1, PD-1, CD3, CD4, CD8, CD45RO, CD57, CD68, FOXP3, granzyme B, and ICOS. Immune-related markers mRNA expression were also assessed. We evaluated the association of OX-40 levels with major clinicopathologic variables, including molecular driver mutations.ResultsOX-40 IHC expression was observed in all tested tumors, predominantly localized in the membrane of the tumor immune infiltrate, and was not associated with a specific clinicopathologic or molecular subtype. High OX-40 expression levels measured by IHC median score were associated with better overall survival (OS) (p = 0.002), independent of CD3/CD8, PD-L1, and ICOS expression. High OX-40 IHC score was associated with increased expression of immune-related genes such as CD3, IFN-gamma, ICOS, CD8, CXCL9, CXCL10, CCL5, granzyme K.ConclusionsHigh OX-40 IHC expression in the tumor immune infiltrate is associated with favorable prognosis and increased levels of immune-related genes including IFN-gamma in patients with surgically resected stage I-III NSCLC. Its prognostic utility is independent of PD-L1 and other common markers of immune activation. High OX-40 expression potentially identifies a unique subgroup of NSCLC that may benefit from co-stimulation with OX-40 agonist antibodies and potentially enhance the efficacy of existing immune checkpoint therapies.
Highlights
OX-40 co-stimulatory signaling plays a role in mounting anti-tumor immune responses and clinical trials targeting this pathway are ongoing
It is of particular interest as treatment with an activating anti-OX-40 monoclonal antibody augments T-cell differentiation and cytolytic function leads to enhanced anti-tumor immunity against a variety of tumors [11]
OX-40 protein expression was localized in the membrane of the tumor immune infiltrating cells in the non-small cell lung cancer (NSCLC) samples
Summary
OX-40 co-stimulatory signaling plays a role in mounting anti-tumor immune responses and clinical trials targeting this pathway are ongoing. The interaction between OX-40 and the OX-40-ligand supplies a co-stimulatory signal for T-cell proliferation in a CD28-independent manner [8] in autoimmune diseases [9] and graft-versus-host disease [10]. It is of particular interest as treatment with an activating (agonist) anti-OX-40 monoclonal antibody (mAb) augments T-cell differentiation and cytolytic function leads to enhanced anti-tumor immunity against a variety of tumors [11]. OX-40 expression on tumor-infiltrating lymphocytes (TIL) correlates with improved survival in several human cancers such as cutaneous melanoma and colorectal cancer, suggesting that OX-40 signals may play a critical role in establishing an anti-tumor immune response [12, 13]
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