Anti-tumor immunity induced by ectopic expression of viral antigens is transient and limited by immune escape

Abstract

Immunotherapeutic treatments in head and neck cancer clinical trials include cancer vaccines targeting foreign viral antigens or mutational neoantigens derived from cancer-expressed proteins. Anti-tumor immune responses place cancer cells under selective pressure to lose or downregulate target antigens; therefore, vaccination against virus-or host-"driver" oncogenes are proposed as a strategy to overcome immune escape. Herein, we demonstrate the impact of immunogenic viral antigens on anti-tumor response and immune editing in MOC2-E6E7, a syngeneic murine oral cancer cell line expressing HPV-16 E6 and E7 oncoproteins. Using orthotopic syngeneic models, we observed in vivo tumor growth kinetics of MOC2-E6E7 is delayed in immunocompetent mice compared to parental MOC2 tumors. In contrast, tumor growth remained similar in Rag1 -/mice lacking adaptive immunity. MOC2-E6E7 tumors demonstrated an "inflamed" or immune-activated tumor microenvironment and greater infiltration of CD8 + T cells compared to MOC2. By real-time PCR, we detected downregulation of E6 and E7 genes in MOC2-E6E7 tumors only in immunocompetent mice, suggesting the loss of ectopic viral antigen expression due to immune editing. We then assessed the efficacy of a biomaterials-based mesoporous silica rod (MSR) cancer vaccine targeting HPV-16 E7 in our model. Vaccination induced robust infiltration of antigen-specific CD8 + T cells, which led to tumor growth delay and modestly prolonged survival in MOC2-E6E7 tumors. Increased efficacy was seen in a separate head and neck cancer tumor model, mEER, which obligately expresses E7 antigen. Collectively, our data highlight the need for both immunogenicity and 'driver' status of target antigens to be considered in cancer vaccine design.

HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING

“…NLRX1 suppresses STING-mediated immune detection of E7-expressing tumors in vivo. Recently, we characterized a new HPV16 E6/E7-expressing HNSCC mouse model, MOC2-E6/E7, which is syngeneic to C57BL/6 (14,24,38). These tumors grow aggressively and are completely resistant to immune checkpoint blockade therapy (14,39).…”

The promise of Immuno-oncology: implications for defining the value of cancer treatment

“…I-O therapies can also evolve over time, broadening and deepening anti-tumor immunity, preventing the cancer’s ability to escape through the selective growth of variants that can evade immune detection. The rapid co-evolution of tumor cells and immune responses may also result in immunoediting resulting in loss of antigen-specific immunity explaining, in part, IO drug resistance and the need to reconsider the pharmacologic drug class, dosing, schedule and combination to optimize anti-tumor activity [10].…”

Immune microenvironment modulation unmasks therapeutic benefit of radiotherapy and checkpoint inhibition

“…2e). To further assess the antigen specificity of the immune memory response we utilized a dual flank rechallenge model using a HPV-negative HNSCC tumor model, MOC2, made with or without exogenous expression of E6 and E7 HPV antigens [35–37]. In CPR treated mice 100 days post-clearance, we re-challenged with parental MOC2 tumors on the initial tumor-bearing flank and MOC2 tumors transfected with E6 and E7 HPV viral oncoproteins (MOC2-E6/E7) on the opposing flank.…”

“…MOC2 cell line was obtained from Dr. Uppaluri at Brigham and Women’s Hospital/ Harvard Medical School and maintained as previously described [35, 36]. MOC2 E6/E7 cell line expressing HPV16 E6 and E7 was obtained from Dr. Simon Young at UT Health and was maintained similar to the parental MOC2 cell line [37]. B16-F0 cell line was purchased from American Type Culture Collection (ATCC) and maintained according to manufacturer instructions (DMEM high-glucose with 10% fetal bovine serum and 1% penicillin/streptomycin).…”