Cancer immunogenomic approach to neoantigen discovery in a checkpoint blockade responsive murine model of oral cavity squamous cell carcinoma

Abstract

Head and neck squamous cell carcinomas (HNSCC) are an ideal immunotherapy target due to their high mutation burden and frequent infiltration with lymphocytes. Preclinical models to investigate targeted and combination therapies as well as defining biomarkers to guide treatment represent an important need in the field. Immunogenomics approaches have illuminated the role of mutation-derived tumor neoantigens as potential biomarkers of response to checkpoint blockade as well as representing therapeutic vaccines. Here, we aimed to define a platform for checkpoint and other immunotherapy studies using syngeneic HNSCC cell line models (MOC2 and MOC22), and evaluated the association between mutation burden, predicted neoantigen landscape, infiltrating T cell populations and responsiveness of tumors to anti-PD1 therapy. We defined dramatic hematopoietic cell transcriptomic alterations in the MOC22 anti-PD1 responsive model in both tumor and draining lymph nodes. Using a cancer immunogenomics pipeline and validation with ELISPOT and tetramer analysis, we identified the H-2Kb-restricted ICAM1 P315L (mICAM1) as a neoantigen in MOC22. Finally, we demonstrated that mICAM1 vaccination was able to protect against MOC22 tumor development defining mICAM1 as a bona fide neoantigen. Together these data define a pre-clinical HNSCC model system that provides a foundation for future investigations into combination and novel therapeutics. www.impactjournals.com/oncotarget/

Tumor Membrane Vesicle Vaccine Augments the Efficacy of Anti-PD1 Antibody in Immune Checkpoint Inhibitor-Resistant Squamous Cell Carcinoma Models of Head and Neck Cancer

“…To test whether TMV vaccine inhibits the growth of the highly aggressive MOC2 tumor growth, we administered mice with MOC2 TMV vaccine every five days starting day 3 after tumor challenge and mouse anti-mouse PD-1 antibody (kind gift from Dr. Gordon Freeman) starting on day 8 after tumor challenge, as described in Figure 5 A. The data suggest that MOC2 tumor growth is not affected by anti-PD-1 antibody ( Figure 5 B), which is consistent with earlier studies [ 38 ] and our own studies using rat anti-mouse PD-1 antibody. Interestingly, the TMV vaccine was able to inhibit MOC2 tumor growth and synergized with anti-PD-1 antibody in controlling MOC2 tumor growth and prolonging survival of the mice, with tumors being 10 times smaller in the combination treatment group (~15 mm 2 ) compared to PBS or monotherapy treated after 30 days ( Figure 5 C).…”

“…tumor challenge, as described in Figure 5A. The data suggest that MOC2 tumor growth is not affected by anti-PD-1 antibody ( Figure 5B), which is consistent with earlier studies [38] and our own studies using rat anti-mouse PD-1 antibody. Interestingly, the TMV vaccine was able to inhibit MOC2 tumor growth and synergized with anti-PD-1 antibody in controlling MOC2 tumor growth and prolonging survival of the mice, with tumors being 10 times smaller in the combination treatment group (~15 mm 2 ) compared to PBS or monotherapy treated after 30 days ( Figure 5C).…”

“…MOC2 is a highly aggressive metastatic tumor with negligible or no T cell infiltration in the tumors and is thus termed a "cold" tumor. MOC2 does not respond to anti-PD-1 alone or the combination of anti-PD-1 + anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody therapies [38], indicating it as a representative model for patients who do fail to respond to ICI immunotherapy. To determine whether TMV vaccine also effective against these murine oral cancer (MOC) models, we have prepared TMV vaccine from tumors grown in C57BL/6 mice.…”

NK cells and CTLs are required to clear solid tumor in a novel model of patient-derived-xenograft

“…ICI targeting of immune suppressive pathways are FDA approved for the treatments of many solid tumors, including non-small-cell-lung cancer (NSCLC). However, blocking immune-checkpoint molecules alone does not guarantee tumor eradication by cytotoxic immune cells, as immune cell attack ultimately depends on the recognition of either tumor antigen by T cells, or stress-ligandmediated activation of NK cells (39)(40)(41). This may explain why ICI is most effective in tumors with a high metastatic burden, which presumably results in an abundance of tumor antigens that are stimulatory to the immune system (42).…”

Immune Evasion by Head and Neck Cancer: Foundations for Combination Therapy

“…Due to their inherent genetic instability and high mutagenic rate, HNSCCs routinely transcribe high levels of cancer-specific neoantigens [11]. In a mouse model of oral cavity cancer with high fidelity to human oral cavity cancer, a higher rate of unique tumor neoantigens was associated with responsiveness to immunotherapy [12].…”