(14) Tumor Microenvironment Modulation by Cetuximab and its Contribution to Subsequent Immune-checkpoint Inhibition Therapy in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Abstract: Current clinical and observational evidence supports the EXTREME regimen as one of the standards of care for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) followed by the administration of immune checkpoint inhibitors (ICIs). In addition to the inhibition of the endothelial growth factor receptor (EGFR) pathway, cetuximab-mediated EGFR blockade has been shown to modulate tumor microenvironment (TME) characteristics, such as antibody-dependent cellular cytotoxicity (ADCC) activity, cytotoxic T-lymphocyte (CTL) infiltration into the tumor, anti-angiogenesis activity, and cytokine secretion via associated natural killer (NK) cells. On the other hand, there are reports that nivolumab affects the TME via PD-1 inhibition, IL-10 upregulation via T-cells, MDSC-mediated immune escape induction, and tumor vessel perfusion by promoting CD8+ T-cell accumulation and IFN-γ production in treatment-sensitive tumor cells. Based on the above evidence, the aim of this study is to find a novel treatment strategy for R/M HNSCC focusing on TME modulation by the administration of those recent representative therapeutic agents, cetuximab and nivolumab.
We obtained background evidence regarding the biological effects of cetuximab on response to nivolumab and nivolumab on response to cetuximab in the TME from PubMed database and summarized those findings.
HNSCC treatment using cetuximab increases the frequency of FoxP3+ intratumoral effector Tregs expressing CTLA-4, and targeting CTLA-4+ Tregs using ipilimumab restores the cytolytic function of NK cells, which mediate ADCC activity [1]. Treg-mediated immune suppression also contributes to clinical response to cetuximab treatment, suggesting the possibility of adding ipilimumab or the use of other Treg ablation strategies to promote antitumor immunity. Moreover, in hyper progression disease (HPD), intratumoral frequency of FoxP3+ effector Tregs expressing CTLA-4 increases. Therefore, combination treatment involving cetuximab and an anti-CTLA-4 antibody for R/M HNSCC and HPD after nivolumab administration may be expected to result in a higher tumor-control response.
Another strategy by which TME can be modified using nivolumab is by interfering with MDSC function. Specifically, MDSCs exert their immunomodulatory effects via diverse mechanisms, including Arginase-1-mediated depletion of l-arginine and NO production via nitric oxide synthase 2 (NOS2). It is reported that Arginase-1 starves L-arginine limiting T-cell proliferation. In addition to L-arginine depletion, NO production transforms the TME to promote immune escape. This MDSC-related driven-immune escape cascade contributes to developing HPD, implying that the appropriate control of MDSCs may improve the response rate of ICI treatment. Previous evidence reported that the inhibition of the Notch signaling pathway is associated with reduced MDSC, tumor-associated macrophage, and Treg counts within emerging mouse tumor tissues. Its inhibition significantly inhibits the mRNA and protein expression levels of the most relevant immune checkpoint molecules, PD-1, CTLA4, TIM3, and LAG3, all of which represent targets for approved or developmental ICIs, implying as one of the therapeutic targets [2]. Moreover, recent studies also have demonstrated the potential of combining anti-EGFR with anti-PD-1/PD-L1 therapies to treat tumors and overcome drug resistance. Biologically, this may be partly due to the activation of EGFR signaling, which also modulates antitumor immunity via mechanisms, such as PD-L1 upregulation via the ERK, AKT-mTOR, and STAT3 pathways. These pieces of evidence may explain the biological efficacy of cetuximab followed by ICI treatment.
Here, we suggest the efficacy of using these therapeutic combined strategies for patients with R/M HNSCC and patients who do not respond well to nivolumab administration.

Reference:
1. Jie HB, et al. CTLA-4+ regulatory T cells increased in cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res (2015) 75:2200–10.
2. Mao L, et al. γ-Secretase inhibitor reduces immunosuppressive cells and enhances tumour immunity in head and neck squamous cell carcinoma. Int J Cancer (2018) 142:999–1009.

TME modulation by cetuximab and nivolumab and potential breakthrough treatment strategy using ipilimumab for HPD