CXCL14 suppresses human papillomavirus-associated head and neck cancer through antigen-specific CD8+ T-cell responses by upregulating MHC-I expression

Abstract

Evasion of the host immune responses is critical for both persistent human papillomavirus (HPV) infection and associated cancer progression. We have previously shown that expression of the homeostatic chemokine CXCL14 is significantly downregulated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive head and neck cancer (HNC) cells dramatically suppresses tumor growth and increases survival through an immunedependent mechanism in mice. Although CXCL14 recruits natural killer (NK) and T cells to the tumor microenvironment, the mechanism by which CXCL14 mediates tumor suppression through NK and/or T cells remained undefined. Here we report that CD8 + T cells are required for CXCL14-mediated tumor suppression. Using a CD8 + T-cell receptor transgenic model, we show that the CXCL14-mediated antitumor CD8 + T-cell responses require antigen specificity. Interestingly, CXCL14 expression restores major histocompatibility complex class I (MHC-I) expression on HPV-positive HNC cells downregulated by HPV, and knockdown of MHC-I expression in HNC cells results in loss of tumor suppression even with CXCL14 expression. These results suggest that CXCL14 enacts antitumor immunity through restoration of MHC-I expression on tumor cells and promoting antigen-specific CD8 + T-cell responses to suppress HPV-positive HNC.

The multifarious roles of the chemokine CXCL14 in cancer progression and immune responses

“…Suppression of tumor growth and metastasis by CXCL14 is abolished when NK cells are depleted in mice with melanoma, 34 suggesting that the NK cell activity enhanced by CXCL14 is key for tumor suppression in melanoma. Our studies have also shown that NK cells are recruited by re‐expression of CXCL14 in HPV‐positive HNC cells, and NK cell depletion reverted CXCL14‐mediated tumor suppression 12,62 . In addition, our immunocompetent syngeneic HNC model has revealed that CXCL14 re‐expression also induces chemotaxis of CD4 + and CD8 + T cells.…”

“…In addition, our immunocompetent syngeneic HNC model has revealed that CXCL14 re‐expression also induces chemotaxis of CD4 + and CD8 + T cells. While the depletion of CD4 + T cells shows minimal effects, all mice with a compromised CD8 + T cell repertoire grow tumors, indicating that CXCL14‐mediated tumor suppression is reliant on CD8 + T cells 62 . Further contributing to tumor suppression, we have discovered that CXCL14 increases major histocompatibility complex class I (MHC‐I) expression on the tumor cell surface and activates antigen‐specific CD8 + T cells to kill HPV‐positive HNC cells 62 .…”

“…The Cancer Genome Atlas (TCGA) RNA sequencing and patient survival data were obtained through the Human Protein Atlas (http://proteinatlas.org). Patient survival rates were analyzed using a Kaplan‐Meier estimator and log‐rank P ‐values were calculated as we previously described 62 . Patients of each cancer type were classified into high‐ and low‐expression groups based on the best expression cutoff, which refers to the FPKM value that yields the lowest log‐rank P ‐value [Color figure can be viewed at http://wileyonlinelibrary.com]…”

“…While the depletion of CD4 + T cells shows minimal effects, all mice with a compromised CD8 + T cell repertoire grow tumors, indicating that CXCL14‐mediated tumor suppression is reliant on CD8 + T cells 62 . Further contributing to tumor suppression, we have discovered that CXCL14 increases major histocompatibility complex class I (MHC‐I) expression on the tumor cell surface and activates antigen‐specific CD8 + T cells to kill HPV‐positive HNC cells 62 . These results suggest a potent tumor suppressor function of CXCL14, which could be used as an immunotherapeutic agent to treat cancers.…”

Immune Escape Mechanisms and Their Clinical Relevance in Head and Neck Squamous Cell Carcinoma

“…This impaired HLA class I expression could in most publications be reversed by treatment with respective inhibitors or by IFN-γ [ 56 ]. Furthermore, a link between the expression of the chemokine CXCL14 and HLA class I expression was recently shown [ 57 ], demonstrating the ability of CXCL14 to restore the deficient HLA class I expression in HPV + HNSCC cells. Regarding HLA class II expression, only a minority of HNSCC lesions, but a high frequency of stromal cells expressed HLA class II antigens with higher levels in HPV + compared to HPV - tumors [ 58 ].…”