Remodeling the tumor microenvironment to overcome treatment resistance in HPV-negative head and neck cancer

Abstract

Despite intensive efforts and refined techniques, overall survival in HPV-negative head and neck cancer remains poor. Robust immune priming is required to elicit a strong and durable antitumor immune response in immunologically cold and excluded tumors like HPV-negative head and neck cancer. This review highlights how the tumor microenvironment could be affected by different immune and stromal cell types, weighs the need to integrate metabolic regulation of the tumor microenvironment into cancer treatment strategies and summarizes the emerging clinical applicability of personalized immunotherapeutic strategies in HPV-negative head and neck cancer.

Keywords: HPV-negative; SBRT; Tumor microenvironments; head and neck cancer; immunotherapy; metabolic reprogramming; radiotherapy.

Figure 1

Dynamic composition of the TME. Specialized microenvironments that can be influenced by the genetic/epigenetic background, the tissue of origin, and the components of the tissue, and promote specific effects that are dynamically interconnected. The final outcome results from an integrated response.

Figure 2

Immunosuppressive tumor microenvironment. Direct and indirect alterations in the TME suppress the immune response. Pro-tumor cytokines recruit immunosuppressive cells that prevent antigen presentation, which could be addressed by targeting Tregs. Reduction of pro-inflammatory cytokines generates T cell dysfunction and reduced antigen presentation. CAFs: cancer-associated fibroblasts; DCs: dendritic cells; ICB: immune checkpoint blockade; IL-6: interleukin 6; IL-10: interleukin 10; MDSC: myeloid-derived suppressor cells; TAM: tumor-associated macrophage; TGF-β: transforming growth factor beta; TME: tumor microenvironment.

Figure 3

Metabolic pathways in (A) normal cells, (B) cancer cells, (C) CD8⁺ T cell, and (D) Treg cell . (A): Glycolysis, the conversion of glucose to pyruvate, and the pentose phosphate pathway (PPP), that generates ribose-5-phosphate and NADPH (required for nucleotide synthesis, redox balance, and fatty acid synthesis. Pyruvate can be converted to lactate and secreted or enter the tricarboxylic (TCA) acid cycle in the mitochondria. Fatty acids can undergo fatty acid oxidation and glutamine glutaminolysis, and enter the TCA. The TCA generates NADH and FADH that can enter the electron transport chain (ETC) and contribute to the synthesis of ATP and reactive oxygen species (ROS). Citrate from the TCA can enter the cytoplasm to participate in fatty acid synthesis (FAS). Glutamine metabolism can also synthesize glutathione (GSH); (B): cancer cells increase glycolysis, lactate production, PPP, FAO, FAS, and glutaminolysis. Cancer cells also maintain certain levels of the TCA cycle and oxidative phosphorylation (OXPHOS); (C): CD8⁺ T cells increase glycolysis, fatty acid uptake, FAS, glutamine uptake, glutaminolysis, and glutathione synthesis. The limited entry of pyruvate to the TCA favors the expression of IFNγ; (D): Tregs increase FAO, the TCA cycle, and OXPHOS; maintain PPP and glycolysis to obtain pyruvate, which feeds the increased flux of the TCA cycle and OXPHOS, while the conversion of pyruvate to lactate is restricted. Tregs limit FAS and glutamine metabolism. Increased fluxes are indicated by higher color tones.

Figure 4

Immunomodulation, creating a metabolically permissive microenvironment, and priming the immune system to remodel the tumor microenvironment and elicit a strong immune response.