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Program Number: B187
Session Name: Poster Session

The Efficacy of mTOR Inhibitors in Potentiating the Immune Response in TP53 Mutant Head and Neck Squamous Cell Carcinoma

Victor H Albornoz Alvarez, MD¹; Mark T Knackstedt, MD¹; Srivatsa Vasudevan, MD, MS¹; Tara Moore-Medlin, BS¹; Clint Allen, MD²; Alok Khandelwal, PhD¹; Cherie-Ann Nathan, MD, FACS¹; ¹LSU Health Shreveport; ²National Cancer Institute

Background: TP53 mutant, head and neck squamous cell carcinoma (HNSCC) is characterized by a high rate of treatment failure, often attributed to the tumor's ability to evade immune surveillance. This immune escape is mediated by various mechanisms, including the suppression of cytotoxic T-cell activity within the tumor microenvironment. While immunotherapies targeting the PD-1/PD-L1 axis have demonstrated promise in controlling tumor progression, a significant proportion of patients fail to respond. Therefore, strategies to enhance anti-tumor immunity and overcome resistance to immunotherapy are urgently needed. Emerging evidence suggests that mTOR inhibitors (mTORi) may also modulate immune responses within the tumor. Accordingly, we investigated the effect of mTORi in mediating cytotoxic T-cell activity to promote anti-tumor efficacy in a syngeneic, TP53 mutant HNSCC mouse model. This was performed with varying degrees of T-cell infiltration to elucidate its role in mTORi antitumor activity. Additionally, we explored the mechanism by studying the cytotoxicity of T-cells.

Methods: An in vivo study was conducted utilizing two distinct HNSCC murine models: MOC2-SIINFEKL, characterized by high T-cell infiltration ("immunogenic"), and MOC-2, characterized by low T-cell infiltration ("non-immunogenic"). Mice were inoculated with respective cell lines and randomized to receive either the mTORi everolimus or vehicle. Tumor volume was assessed longitudinally, and a two-way ANOVA was employed to analyze differences in tumor growth kinetics between treatment groups.

Results: Everolimus significantly inhibited tumor growth in the MOC2-SIINFEKL model compared to both the MOC-2 everolimus-treated group (p=0.04 at day 17; p=0.01 at day 26) (Figure 1) and the MOC2-SIINFEKL vehicle group (p=0.0002 at day 21; p<0.0001 at day 26) (Figure 2). No significant difference in tumor growth was observed between the MOC-2 and MOC2-SIINFEKL vehicle groups (Figure 3). Further, treatment with mTORi was associated with a significant increase in cytotoxicity of T cells on poorly immunogenic TP53 mutant HNSCC cells. Moreover, treatment with mTORi significantly attenuated T cells exhaustion.

Conclusion: Our findings demonstrate that everolimus exerts enhanced anti-tumor activity in TP53 mutant, HNSCC models with increased cytotoxicity and T-cell infiltration. This suggests that mTORi may augment immune-mediated tumor control by mitigating T-cell exhaustion. These results support further investigation of mTORi as a strategy to enhance the efficacy of immunotherapy in HNSCC, particularly in patients with tumors exhibiting an immunogenic phenotype.

Figure 1. Tumor volume progression between MOC2-everolimus vs MOC2 SIINFEKL-everolimus groups

Figure 2. Tumor volume growth between MOC2 SIINFEKL everolimus vs MOC2 SIINFEKL vehicle

Figure 3. Tumor growth between MOC2 SIINFEKL vehicle and MOC2 vehicle

 

 

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